L-glutamine, an amino acid that occurs naturally in the body and plays an important role in digestion, has been studied as a potential way to ease side effects in other cancers. But this was the first trial to evaluate it as an anti-cancer therapy in human patients, said Jun Gong, MD, associate professor of Medicine, medical director of Colorectal Cancer at Cedars-Sinai Cancer and first author of the study.

“Current treatment for stage 4 pancreatic cancer is a cocktail of chemotherapy, with overall survival ranging from eight to 13 months,” Gong said. “We found that by adding L-glutamine to this treatment, we increased overall survival to as much as 22 months—and these positive results merit larger clinical trials of this combination.”

In this Phase I clinical trial, investigators studied 16 patients with advanced pancreatic cancer. All patients were treated with a standard chemotherapy combination of gemcitabine and nab-paclitaxel, along with clinical-grade L-glutamine supplements.

“We began the trial in the hope of improving gut health in these patients,” said Neil Bhowmick, PhD, Mark Goodson Chair in Oncology Research, professor of Medicine and Biomedical Sciences, research scientist at Cedars-Sinai Cancer, and senior author of the study. “Patients with pancreatic cancer do not absorb nutrients well, and often develop a condition called cachexia—a loss of weight and muscle that can be fatal. Glutamine is known to help the gut heal.”

Half of the patients in the study maintained their weight, and investigators found a correlation between the way the bacteria in the gut responded to the glutamine and patient outcomes, Gong said.

“At the time of our paper’s publication, the life expectancy of these patients taking glutamine and chemotherapy was more than double the average life expectancy associated with the historical standard of care,” Gong said. “The study did not compare the two options head-to-head, but our result is striking enough for us to advance to a larger randomized trial where patients are given glutamine or not.”

In the lab, investigators also found that cancer cells exposed to high-dose glutamine were particularly vulnerable to chemotherapy, a result in line with the reduction in tumor size seen in patients.

“It is really satisfying to see science from the bench translated so well into patient outcomes,” Bhowmick said.

The supplements used in the study are approved by the Food and Drug Administration for treatment of sickle cell disease, meaning they are federally regulated, Bhowmick and Gong said.

“The survival rate for advanced pancreatic cancer is poor,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “This trial points to a potential new option for optimizing first-line chemotherapy for patients while also opening up a number of new avenues for our physician-scientists to study.”

Additional Cedars-Sinai authors include Hayato Muranaka, So Yung Choi, Mourad Tighiouart, Aleksandr Stotland, Jennifer Van Eyk, Omer H.M. Elmadbouh, Mouad Edderkaoui, Sunao Tanaka, Hideki Furuya, Arsen Osipov, Jeremy Lorber, Sandrine Billet, Stephen J. Pandol, and Andrew Hendifar.

Other authors include Shrikant Bhute, Ezinne R. Aja, Jonathan P. Jacobs, Alexzandra Morris, Johanna ten Hoeve-Scott, and Thomas Graeber.

Funding: This project was funded by the 2019 Tower Cancer Research Foundation Experimental Therapeutics Endowed Fund/Cedars-Sinai Cancer 2019 Developmental Funds for Investigator-Initiated Trials (IITs; J.G.). This project was also supported in part by the NIH National Center for Advancing Translational Sciences (NCATS) UCLA CTSI (UL1 TR001881-01; M.T.) and NCI grants P01CA233452 (M.T., S.J.P., N.A.B.) and U01 grant CA232859-01 (M.T.).

Competing Interest Statement: H.M., N.A.B., J.G. and A.H. have a pending patent related to the work.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

During FY 2026, which ended June 30, more than 9,400 donors supported the academic medical center’s operations, programs and initiatives. Three out of every four of these donors received care at Cedars-Sinai prior to contributing.

“The extraordinary commitment of our donors is a wonderful validation of the dedication and expertise of Cedars-Sinai employees as well as the remarkable generosity of the people we are privileged to serve,” said Peter L. Slavin, MD, president and CEO of Cedars-Sinai and the David and Meredith Kaplan Presidential Chair.

Emma Geller is an example of a patient whose family showed gratitude with a donation. The 13-year-old is cancer-free after being treated for non-Hodgkin’s lymphoma at Cedars-Sinai Guerin Children’s. Despite financial strain caused by major damage to their home in the January 2025 Palisades Fire, the Gellers remain committed to their annual support of pediatric hematology/oncology research and pediatric nursing at Cedars-Sinai.

“Our daughter received such tremendous care from amazing doctors, and we wanted to know how we could give back,” said Jordan Geller, Emma’s father. “If there was a way to make other people’s lives a little better as they were going through something like this, we wanted to do it.”

Some of the most meaningful philanthropic investments in Cedars-Sinai are unrestricted gifts to The Fund for Cedars-Sinai.

One example of unrestricted support this past year was a $10 million gift from the Ashkenazy family, providing flexible resources that can be directed where they will have the greatest impact. This support enables Cedars-Sinai to respond to emerging needs, invest in strategic priorities and pursue promising opportunities, helping advance our mission both now and in the years ahead.

“Unrestricted gifts are the fuel powering vital community health initiatives and the highest level of patient care,” said Heather Renshaw Vučetin, vice president of Development for Cedars-Sinai. “Gifts of every size improve our community’s health, which is priceless.”

Other recent major gifts included but were not limited to:

• The Cedars-Sinai Cayton BRCA Center: A $30 million gift from the Cayton Goldrich Family Foundation to create a center for research, diagnosis and comprehensive treatment of illnesses linked to mutations in the BRCA1 and BRCA2 genes.
• The Cedars-Sinai Holoman Health Equity Center: A $13 million gift from Eric and Terri Holoman to establish a center that will shape the future of equitable healthcare at Cedars-Sinai.
• A generous bequest from the estate of Joanna Carson, demonstrating the enduring impact of planned giving. By including the organization in her estate plans, Carson created a legacy that will strengthen our mission for future generations.

“Philanthropic support is a powerful catalyst for healing,” said Arthur J. Ochoa, JD, senior vice president and chief advancement officer for Cedars-Sinai. “Whether expressed through volunteering or making a financial gift, the simple act of giving is fundamental to Cedars-Sinai’s vision to make a meaningful and lasting difference in the Los Angeles community and beyond.”

Read more from Cedars-Sinai Stories and Insights: Strengthening Children’s Health

The protein restores the blood stem cell niche—the specialized environment that supports blood-forming stem cells—allowing the bone marrow to resume producing the blood cells the body needs.

Their preclinical study, published in Blood, could yield future treatments that help cancer patients recover faster after chemotherapy and radiation.

“The mechanisms that govern how the blood stem cell niche recovers after injury are not well understood,” said John Chute, MD, director of the Division of Hematology and Cellular Therapy at Cedars-Sinai and senior author of the study. “We identified a mechanism that stimulates niche recovery, which opens an exciting avenue to help patients replenish their entire blood system after chemotherapy or radiation.”

Chute compared the niche to the soil in a garden in which blood stem cells—which generate all of the body’s blood cells—blossom or grow. The niche is made up of several types of cells that tend to the blood stem cells, spurring them to divide and multiply so that they can replace blood cells that are damaged or lost.

“Chemotherapy and radiation therapy cause severe DNA damage to the niche cells,” Chute said. “The blood stem cells can’t regenerate because of this damage to their ‘soil,’ and this depletes the patient’s blood count for weeks.”

For patients, this means debilitating fatigue and increased risk of infection, bleeding and prolonged hospitalization.

Investigators found that a protein called R-spondin 2, which amplifies the signaling in cells that line blood vessels in the bone marrow, speeds up the recovery of the niche. 

When investigators treated laboratory mice that had been exposed to total body irradiation with R-spondin 2, the blood stem cell niche—specifically the cells lining the blood vessels in the niche—recovered more quickly than in untreated mice.

A key and surprising finding was that R-spondin 2 acted on the vascular niche cells, rather than the blood stem cells themselves.

Chute said that these findings may open the door to future research focused on the discovery and augmentation of mechanisms for niche repair. Targeting such mechanisms could accelerate the recovery of patients receiving chemotherapy or undergoing stem cell transplantation.

“Our outcomes for patients undergoing blood and marrow transplant are exceptional,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “This type of translational research can yield further improvements for those patients and all patients undergoing chemotherapy or radiotherapy.”

Additional Cedars-Sinai authors include Vanessa N. Montinelli, Samantha Grohe, Xue Ying Song, Jacqueline Turnlund, Hannah Hackbart, Joshua Sasine, Morgan Brady, Masahiro Muraoka, Rucha Kadam, Flavia D. Cavicchioli, Sage Kang, Ashley Dawson, Mimoli Uehara, Courtny Dizon, Theresa Krack, Peibin Yue, and Yuwei He.

The paper’s other author is Kurt D. Hankenson, University of Michigan.

Funding: This work was funded, in part, by NIAID awards U01 AI159622 (PI: John Chute), R21 AI193964 and NHLBI award R01 HL086998 (PI: John Chute).

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

An average woman has about a 13% chance of developing breast cancer during her lifetime, according to the National Cancer Institute. A BRCA1 or BRCA2 gene mutation raises breast cancer risk to 30%-70%, and BRCA testing is recommended for women with personal or family history of certain cancers, a known BRCA mutation in the family, or Ashkenazi Jewish ancestry.

“While most women who undergo genetic testing do not test positive for a cancer-risk-increasing BRCA mutation, they have generally been referred for testing because of strong personal or family cancer history,” said Fahima Dossa, MD, PhD, surgical oncologist at Cedars-Sinai Cancer and lead author of the study. “Future cancer risk for these women has not been well studied, and our findings are the first to calculate that risk so that we can better guide all women who undergo BRCA testing.”

Looking at the health records of almost 16,000 women who underwent BRCA testing in Ontario, Canada, from 2007 to 2016, investigators found that women who tested negative for a BRCA gene mutation still had a 25% lifetime risk of developing breast cancer.

And lifetime risk for those with a variant of unknown significance, which means little is known about that particular variant, was 30%, according to the findings.

Each patient’s individual risk for breast cancer was substantially affected by their family history. Among women who tested positive for a BRCA mutation, breast cancer risk varied from roughly 56% to 86%, depending on the number of immediate family members who had breast or ovarian cancer, the study found.

“Based on these findings, a physician might recommend more frequent mammograms or breast MRI to a BRCA-positive patient in their 50s or 60s with no family history of breast cancer, but suggest preventive mastectomy as an option for a young BRCA patient with several cases of breast cancer in the family,” Dossa said.

Dossa said that the only women in the study with the same breast cancer risk as the general population were those who had family history of cancer and a known BRCA mutation in the family, and were tested for that specific mutation but did not have the mutation.

“This study is a reminder to patients about the importance of having discussions with their doctors about genetic test results,” Dossa said. “We finally have some data to help inform those conversations.”

In July, Cedars-Sinai opened the Cedars-Sinai Cayton BRCA Center to provide coordinated screening, guidance and treatment to patients with BRCA mutations.

“Our leading-edge research supports our efforts to care for and improve outcomes for these patients,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “Connecting science with cancer care is at the heart of what we do.”

Other study authors include Kelly Metcalfe, RN, PhD; Zharmaine Ante, MSc; Ning Liu, PhD; Jordan Lerner-Ellis, PhD; Andrea Eisen, MD; and Nancy N. Baxter, MD, PhD.

Funding: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This study also received funding from the Canadian Cancer Society (grant #315358). This work was also supported by the Canadian Institutes of Health Research (CIHR) grant funding no #148470.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

The preclinical study was published in Cell Reports Medicine. 

“Our study is the first to show how metabolites produced by select bacteria can induce changes in the body’s immune response when the body is fighting cancer,” said Ze’ev Ronai, PhD, director of the Translational Research Institute at Cedars-Sinai, professor of Surgery and senior author of the study. “Previous research established that gut bacteria affect the immune system and can help fight cancer. Our new findings are an important step forward because they give us a specific metabolite that can be used for future therapies.” 

The investigators focused on B. rodentium in the guts of mice and a related bacteria species, B. uniformis, in the guts of humans. When these bacteria break down the amino acid tryptophan, they produce different forms of metabolites called indoles. 

In laboratory mice, investigators found that treatment with B. rodentium restricted the growth of melanoma and colon, breast and pancreatic cancers, and that treatment with indole on its own restricted the growth of melanoma.

“Indole was more effective against these tumors than other metabolites produced by tryptophan breakdown, which are used in immunotherapies,” said Ximena Diaz Olea, a research scientist in the Ronai Lab and first author of the study. 

The investigators also looked at data from human patients who were responding well to immunotherapy for melanoma. In these patients, investigators found increased levels of the enzymes used to produce indole, suggesting higher levels of indoles were contributing to the patients’ good outcomes. 

“We are now evaluating whether increasing the levels of indoles in the gut would be sufficient to inhibit cancer,” Ronai said. “We hope to turn these findings into a therapy that will benefit patients.”

Investigators say this might be possible by giving patients capsules containing B. uniformis, then following up with nutrients to increase the bacteria’s reproduction and indole levels in the gut.

While this study focused on B. uniformis and B. rodentium, as many as 20 different bacteria species produce the enzyme that creates indole, opening further avenues for exploration, Ronai said. 

“These findings provide the foundation for modes of treatment that could complement or replace existing ones,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “This type of translational science paves the way toward new options for patients.” 

If investigators are successful at translating their findings into an anticancer therapy, Ronai said that it would likely be useful against many cancer types, as the immune cells bolstered by indole are effective against many cancers.

Additional Cedars-Sinai authors include Ximena Diaz Olea, Aagam Shah, Hyungsoo Kim, Ashok Kumar Sharma, Anthony Martin, Mark B. Faries, Omid Hamid, Suzanne Devkota, and Simon Knott.

Other authors include Kristin Beede, Gabriel Pereira, David Scott, Christopher Petucci, Eric Martens, Dmitri Rodionov, Miguel P. Martinez, Tongwu Zhang, Andrei Osterman, Emile E. Voest, Nadim J. Ajami, Jennifer Wargo, and Amanda E. Ramer-Tait.

Funding: This work was supported by the Cedars-Sinai shared resources in genomics, vivarium and microbiome studies; NCI grant R35CA197465 (to ZAR); the Hervey Family / San Diego Foundation (to ZAR); grant R21CA249822 (to ART and HK); and the Buffett Cancer Center funds (to ART) via NCI grant CA036727.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Breast tumors are currently classified into basic subtypes such as HER2-positive and triple-negative. Based on a tumor’s subtype, doctors can prescribe chemotherapy, immunotherapy or other treatments to shrink the tumor before a patient undergoes surgery to remove it. This can allow some patients to have a lumpectomy rather than a full mastectomy.

Presurgical treatment, also called neoadjuvant treatment, can also help kill cancer cells that have spread beyond the breast, which can help prevent cancer from returning.

“The issue is that a single breast tumor can include many cancer subtypes, but current tests classify the whole tumor as one,” said Eytan Ruppin, MD, PhD, deputy director of the Translational Research Institute at Cedars-Sinai and co-corresponding author of the study. “With BRIDGE, we use gene activity to measure the various subtypes within a tumor and better pair patients with the most effective presurgical treatment.”

Together with the composition of the tumor, BRIDGE provides a score that tells clinicians how likely a patient is to respond to a given presurgical treatment. The tool analyzes the same tumor biopsy samples physicians routinely take when a patient is diagnosed.

“We addressed the most common presurgical treatments given in the major breast cancer subtypes,” said Thomas Cantore, PhD, a postdoctoral scientist in the Ruppin lab and co-corresponding author of the study. “Applying BRIDGE to data from hundreds of patient samples whose cancer type and treatment response were known, we found that it accurately predicts which patient may or may not respond to which therapy.”

Building on the work of others on Ruppin’s team, the investigators next took BRIDGE a step further.

“Our second step was to apply AI tools to BRIDGE to create BRIDGE-Slide,” said Nishanth Ulhas Nair, PhD, a research scientist in the the Jim and Eleanor Randall Department of Surgery and co-corresponding author of the study. “Rather than requiring costly genomic sequencing of the tumor, BRIDGE-Slide can infer the makeup of a tumor from an image of the biopsy slide. This saves time, and thousands of dollars, and could help democratize precision oncology, making personalized breast cancer treatment accessible to all.”

The next step for investigators is to further test BRIDGE and BRIDGE-Slide in clinical trials, Cantore and Nair said.

“These biopsy slides are a gold mine of information,” Cantore said, “and we are focused on leveraging them.”

Additional Cedars-Sinai authors include S.R. Dhruba, E. Campagnolo, J. Levy, K. Yao, I. Liao, and Y. Yuan.

Other authors include D-T. Hoang, L.R. Pal, A. Stemmer, T-G. Chang, E. Shulman, J.S. Lee, S.M. Stemmer, S-J. Sammut, S. Lipkowitz, P.S. Rajagopal, M. Filipits, and C. Caldas.

Funding: This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI). The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. This research is partially supported by a grant of the Korea-US Collaborative Research Fund (KUCRF), funded by Ministry of Science and ICT and Ministry of Health & Welfare, Republic of Korea (grant number: RS-2024-00468417). This work used the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Andrew Hendifar, MD, professor of Medicine and medical director of the Cancer Clinical Trials Office and the Gastrointestinal Oncology Disease Research Group at Cedars-Sinai, was a principal investigator on the trial and a co-author of the study, which was sponsored by Revolution Medicines, makers of the new drug. He sat down with the Cedars-Sinai Newsroom to talk about the study results.

How does this new drug work?

The medication, called daraxonrasib, is the first drug that targets cancer-causing mutations in pancreas cells.

The drug targets a mutation in the KRAS gene, part of the RAS genetic family. KRAS mutations are present in 92% of pancreatic cancers. KRAS genes normally act as an “on-off” switch for cell growth. Mutated KRAS genes are stuck in the “on” position and send out a signal that causes cells to divide and grow uncontrollably, allowing cancer to form.

Daraxonrasib blocks the KRAS signal by fitting into a keyhole-type spot on the gene. That spot has a complex shape and is difficult to reach within the cell. The drug gets around this problem by using a “passenger protein” as a Trojan horse. When the cell allows this protein in, daraxonrasib tags along.

Why are these clinical trial results so groundbreaking?

There are no targeted treatments approved for pancreas cancer, and we haven’t had any significant progress for a long time. We've only come up with different chemotherapy combinations, and those are only moderately effective. This new treatment is staggeringly better than chemotherapy. Usually, when we think of an improvement in pancreatic cancer survival, we think of 25% improvement. This medication actually doubled survival in patients with advanced disease. We have patients who participated in the trial who are still alive, which is unheard of because the five-year survival rate for pancreatic cancer patients is only 13%-14%. If the drug is approved by the FDA, it will most likely become the new standard of care for advanced pancreatic cancer and could replace chemotherapy as a first-line treatment.

What comes next?

We are now testing the drug in patients with earlier-stage pancreatic cancer, prescribing it while their tumors are still operable and before their cancer spreads.

Could daraxonrasib be effective against other cancer types?

RAS mutations are one of the most common cancer-causing genetic mutations, and the drug is now being studied in several cancer types. I think it's going to work especially well in tumors that are primarily RAS driven, including colon cancer and lung cancer. It might also work in other cancer types in combination with drugs targeting other genetic mutations, but further research is needed.

How will this discovery change cancer science?

This is a win for the field. Until now we have been focused on immune therapies that might make tumors more vulnerable to the body’s immune system, and on finding new chemotherapy combinations that kill cancer cells.

This new treatment has given us a new focus, and I think it will spur a lot of scientific discovery over the next few years. There have only been a handful of KRAS researchers and their relevance to therapy was always questioned. That is about to change.

The most important next step for the field is to better understand the biology of cancer. We know that many pancreatic tumors will eventually become resistant to daraxonrasib, and we need to understand how this happens. We also need to identify additional genetic pathways and treatments that can target them. That’s how we will turn pancreas cancer from a deadly, deadly cancer into something we can manage—and one day, even cure.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Andrew Hendifar, MD, medical director of the Cedars-Sinai Cancer Clinical Trials Office and professor of Medicine, is available to discuss late-breaking, embargoed results of a trial of a new therapy for advanced pancreatic cancer, as well as Phase II results from a trial of a combination therapy that targets specific genetic mutations in pancreatic cancer cells.

Additional Cedars-Sinai Experts

Leslie Ballas, MD, professor of Radiation Oncology, will participate in a panel discussion and can discuss evidence related to use of biomarkers or circulating tumor DNA in treatment decisions for patients with muscle-invasive bladder cancer.

Fahima Dossa, MD, PhD, a surgical oncologist, will present research on which patients with high-risk localized soft tissue sarcoma are most likely to benefit from chemotherapy.

Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle, will present a post hoc analysis of the EMBARK trial in advanced prostate cancer, detailing testosterone recovery following treatment suspension. Freedland can also discuss research from his lab on use of olaparib, an enzyme blocker, in metastatic castration-resistant prostate cancer, and statin use in prostate cancer patients receiving hormone treatment after prostate-removal surgery.

Lawrence Liu, MD, a hematology oncologist, will present research on recent advances in CAR T-cell therapies for patients with relapsed multiple myeloma. The work involves mezigdomide, part of a new drug class in myeloma, following infusion with idecabtagene vicleucel, a genetically modified CAR T therapy derived from the patient’s own cells.

Arsen Osipov, MD, associate professor of Medicine and medical director of Pancreatic Cancer, can discuss research from his lab on the comprehensive molecular profiles associated with variants of the KRAS gene and patient survival in pancreatic cancer. KRAS mutations are found in more than 90% of pancreatic cancer cases.

Karen Reckamp, MD, professor of Medicine and director of the Division of Medical Oncology, can discuss the treatment landscape for non-small cell and small cell lung cancer. She can explain research from her lab on a machine learning approach for predicting immune-related pneumonitis, a noninfectious lung inflammation that can occur following treatment with immune checkpoint inhibitors. She can also speak about new data from Lung MAP, a clinical trial designed to efficiently test treatments for advanced non-small cell lung cancers. And she will make a presentation on support of academic nonclinical efforts for cancer investigator faculty at the Association of American Cancer Institutes.

Kamya Sankar, MD, assistant professor of Medicine and co-director of the Thoracic Disease Research Group, will present an analysis of factors associated with early cachexia—also known as cancer wasting disease—in metastatic non-small cell lung cancer. She can also speak about treatment of both non-small cell and small cell lung cancer.

From The Angeles Clinic and Research Institute

Mark Faries, MD, surgical oncologist and professor of Surgery, can discuss a five-year update from the KEYNOTE-942 study in resected melanoma and a new study of lymph node resection versus therapeutic dissection in advanced melanoma, as well as recurrence in advanced melanoma across time.

Erwin Grussie, MD, a hematology oncologist, can discuss results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study testing targeted therapies in patients with solid tumors.

Omid Hamid, MD, professor of Medicine and chief of Translational Research and Immuno-Oncology, will present results from a study of a medication that blocks the action of cortisol in patients with advanced solid tumors, as well as a study of causes of limited immunotherapy response in melanoma. He can also discuss new results from three trials of therapies in advanced melanoma.

Inderjit Mehmi, MD, a hematology oncologist, can discuss the association of prior immunotherapy treatment with limited response to subsequent immunotherapy in melanoma.

Media Contact

To schedule an interview, contact Christina Elston at christina.elston@cshs.org or 626-298-0702.

The new tool, called Path2Space, predicts gene expression across the tumor area based on digital images of biopsy slides, which contain thin slices of tumor tissue that can be examined under a microscope.

Because tumors do not have the same composition and gene expression throughout, Path2Space predicts what is known as “spatial” gene expression, estimating it at many different points within the tumor. The process takes only minutes and costs significantly less than conventional spatial gene expression profiling, which typically takes several weeks and costs thousands of dollars.

“This tool makes two major contributions,” said Eytan Ruppin, MD, PhD, deputy director of the Translational Research Institute at Cedars-Sinai and senior author of the study. “It will enable us and others to study larger datasets and understand the spatial structure of tumors. But what really motivates me is that, if we can successfully validate the tool in clinical trials, it could improve cancer care for patients.”  

Investigators “trained” Path2Space using data from a large group of patients with breast cancer, where the biopsy slides and spatial sequencing were both available. They then tested the tool on three additional patient datasets to validate its performance.

“For each sample, we looked at the actual, measured gene expression and compared it with our tool’s prediction,” said Eldad Shulman, PhD, co-first author of the study and a research fellow at the National Cancer Institute, who will soon join Ruppin's lab as a research scientist. “For each sample, we predicted the spatial expression of almost 5,000 genes, and the predictions matched the measured expression well across all three patient groups.”

Path2Space is also designed to help scientists discover new biomarkers that could guide treatment decisions and identify patients at higher risk of poor outcomes.  

“The tool looks at characteristics within the tumor, such as whether a gene is expressed in some areas of the tumor and not others,” said Emma Campagnolo, co-first author of the study and a research fellow in Ruppin’s lab. “We found specific spatial patterns of gene activity in tumors that predict how patients respond to treatment.”

Identifying spatial biomarkers is challenging, Shulman said, because the high cost of spatial profiling by traditional methods means very little of this data is available.

“Before we developed Path2Space, the largest cohort we could find to study the spatial organization of the tumor environment was about 30 patients,” Shulman said. “With this tool, we can study slides from thousands of patients. Path2Space is tapping into the potential of spatial biology in a way that has not been possible until now.”

Path2Space could be applied to other cancer types once it is trained on the correct data, and the lab is finalizing a study applying it to head and neck cancer, Campagnolo said. The team is also working to make the tool more precise. It currently looks at groups of 10 to 20 cells together, and the goal is to eventually be able to assess individual cells.  

“With the help of clinical collaborators, we next want to bring Path2Space into clinical trials,” Ruppin said. “It represents an exciting development in a growing field and has to be tested carefully. But we are hopeful that it could make an impactful contribution to science and to patient care.”

Robert Figlin, MD, interim director of Cedars-Sinai Cancer, noted that translational research is a hallmark of the institution.

“The development of tools that apply leading-edge science to patient care is the best way to serve our patients—and to improve cancer care on a global scale,” Figlin said.

Additional Cedars-Sinai authors include Yuan Yuan, Karine Sargsyan, and Simon R.V. Knott.

Other authors include Roshan Lodha, Youngmin Chung, Amos Stemmer, Thomas Cantore, Beibei Ru, Tian-Gen Chang, Sumona Biswas, Saugato Rahman Dhruba, Sumeet Patiyal, Sushant Patkar, Andrew Wang, Ranjan K. Barman, Chuhan Wang, Rohit Paul, Sarath Chandra Kalisetty, Tom Hu, MacLean P. Nasrallah, Ellis Patrick, Jean Yang, Amy Plotkin, Padma Sheila Rajagopal, Stephen-John Sammut, Stanley Lipkowitz, Peng Jiang, Carlos Caldas, Kenneth Aldape, Joo Sang Lee, and Danh-Tai Hoang.

Funding: This research was supported by the Intramural Research Program of the NIH, NCI, and the Center for Cancer Research. The contributions of the NIH authors were made as part of their official duties, as NIH federal employees are in compliance with agency policy requirements and are considered works of the U.S. government. This research was also partially supported by a grant of the Korea-United States Collaborative Research Fund, funded by the Ministry of Science and ICT and the Ministry of Health and Welfare, Republic of Korea (grant number: RS-2024-00468417; Y.C. and J.S.L.), and by an Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korea government (MSIT) (RS-2019-II190421, AI Graduate School Support Program, Sungkyunkwan University; Y.C. and J.S.L.). This work has utilized the computational resources of the NIH HPC Biowulf cluster.

Competing interests: E.D.S., E.M.C. and E.R. are listed as inventors on a provisional patent (application no. 63/703,060, United States, 2024) filed based on the methodology outlined in this study. E.R is (non-paid) member of the scientific advisory boards of Pangea Biomed (divested), GSK Oncology and the ProCan project. E.R is a founder of MedAware Ltd. The other authors declare no competing interests.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Through more than 20 talks, panels, symposia and poster presentations, they will cover topics ranging from cancer biology to the tumor microenvironment, biomarkers that can guide cancer treatment, clinical trial results, and the role of AI in precision oncology.

Late-Breaking Presentation

Inderjit Mehmi, MD, medical oncologist at Cedars-Sinai The Angeles Clinic and Research Institute, will deliver a late-breaking oral presentation about an ongoing Phase I/IIa study of the immune checkpoint inhibitor GV20-0251 in patients with advanced melanoma that is resistant to anti-PD1 and other standard therapies. The presentation builds on clinical data presented at ASCO 2025 and will report translational findings from the study.

Additional Cedars-Sinai Cancer Experts and Topics

Eytan Ruppin, MD, PhD, an investigator at the Translational Research Institute and the Jim and Eleanor Randall Department of Surgery, will chair an Advances in Technology session exploring approaches for harnessing AI to learn about the spatial organization of human tissues. Speakers will describe computational approaches to spatial omics experiments, recent studies on developing agents that facilitate the analysis and characterization of pathology slides and spatial transcriptomics data, and ways to infer spatial biology and cancer treatment response biomarkers directly from histopathology slides.

Sergei Grivennikov, PhD, professor of Medicine and Biomedical Sciences, will co-chair a mini-symposium on the tumor microenvironment and its role in tumor evolution and immune system evasion.

Karen Reckamp, MD, a thoracic medical oncologist and director of the Division of Medical Oncology, will present final results from Pragmatica-Lung, a prospective randomized clinical trial with a pragmatic design that evaluated ramucirumab plus pembrolizumab versus standard of care in more than 800 patients with stage 4 or recurrent non-small cell lung cancer.

Cedars-Sinai investigators will also present research on:

• New understanding of and treatments for breast cancer
• Disparities in heart disease deaths among breast cancer patients
• Antitumor responses in pancreatic and breast cancer
• Radiation and antitumor therapies in prostate cancer
• Immune rejection and antitumor activity in bile duct cancer
• The tumor microenvironment’s role in pancreatic cancer spread

Experts Available to Comment

Cedars-Sinai investigators are available to discuss their work and other news coming out of the meeting. To schedule an interview, contact Christina Elston at christina.elston@cshs.org or 626-298-0702.

Ulcerative colitis is a type of inflammatory bowel disease (IBD) that causes chronic inflammation and sores in the colon.

“Ulcerative colitis greatly increases a person’s risk of developing colorectal cancer, but we don’t have a noninvasive way to determine how great each patient’s risk might be,” said Hajar Hazime, PhD, a project scientist in the Abreu Lab at Cedars-Sinai and co-first author of the study. “Undergoing frequent surveillance colonoscopies can help, but preparing for that procedure is especially difficult for someone with ulcerative colitis.”

Additionally, colonoscopy results can be inconclusive, forcing the physician and patient to decide whether to remove all or part of the colon to prevent cancer from developing, Hazime said. Investigators hoped to find a more conclusive and less invasive way to screen these patients.

“Our physician-scientists are continually working to improve cancer screening for our patients,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “We treat more than 60 types of cancer, but our ultimate goal is prevention.”

Each person’s gut is populated with trillions of microbes—bacteria, viruses, fungi and other organisms too small to see with the naked eye. These interact with each other and appear to influence several aspects of a person’s health, including IBD.

Hazime said that these microbes use QSMs to communicate and coordinate their behavior, and that a goal of the study was to determine whether QSMs play a role in causing colon cancer in patients with ulcerative colitis.

When the investigators examined blood samples from human patients with ulcerative colitis and conducted experiments using colon organoids and laboratory mice, they found:

• In the blood of ulcerative colitis patients, there were higher levels of QSMs in patients at higher risk for cancer, who had experienced symptoms for 10 years or longer, than in patients at lower cancer risk, with symptoms for five years or less.
• In colon organoids—tiny clusters of cells that mimic some functions of the human colon—exposure to QSMs caused inflammation, which is a risk factor for tumor development. Because organoids do not contain gut microbes, this showed that elevated QSM levels and the activity of microbes they regulate can increase cancer risk.
• In laboratory mice with a condition that mirrors ulcerative colitis, investigators found higher levels of QSMs in the blood of those that developed tumors than in those that did not. Also, mice exposed to extra levels of QSMs developed more tumors, more quickly, than those not exposed.

“These results show us that quorum sensing molecules are not only associated with colon cancer risk in patients with ulcerative colitis, but that they actually contribute to the formation of these tumors,” said Maria T. Abreu, MD, executive director of the F. Widjaja Inflammatory Bowel Disease Institute and co-corresponding author of the study. “That makes these molecules a potential way to screen patients for cancer risk, but also a possible target for reducing risk.”

Investigators will next focus on pinpointing how QSMs contribute to tumor formation, studying the molecules as a biomarker to predict cancer development, and finding ways to target these molecules to disrupt cancer development, Abreu said.

Additional Cedars-Sinai authors include Irina Fernández, Katerina M. Faust, and Maria A. Quintero.

Other authors include Gregory O’Connor, Juan F. Burgueño, Ana M. Santander, Nivis Brito, Yuguang Ban, Sapna K. Deo, and Sylvia Daunert.

Funding: This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099076) and the Micky & Madeleine Arison Family Foundation Crohn's & Colitis Discovery Laboratory to MTA as well as from the National Institutes of Health (R01GM127706) and the Department of Defense (W81XWH-20-1-0697) to SD and SKD and the Lucille P. Markey Chair in Biochemistry and Molecular Biology to SD.

Disclosures: MTA is a consultant or on the advisory board of the following companies: AbbVie Inc., Alimentiv Inc., Amgen, Bristol Myers Squibb, Eli Lilly and Company, Genetech, Gilead Sciences, Janssen Pharmaceuticals, Pfizer Pharmaceutical, Takeda Pharmaceuticals, and UCB Pharma.

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If validated in further studies, the artificial intelligence-based platform could be used to improve treatment selection in virtually any cancer type. Results from a study of the platform’s effectiveness are published in the Journal of Clinical Oncology.

“Currently, we have no conclusive data to show which of the two approved chemotherapy regimens for patients with advanced pancreatic cancer is more effective,” said Andrew Hendifar, MD, medical director of Pancreatic Cancer at Cedars-Sinai Cancer and first author of the study. “So we start with one, do our best to quickly gauge the patient’s response, and switch if needed.”

The problem with this, Hendifar said, is that putting an ill patient on a chemotherapy regimen that isn’t working worsens their health rather than improving it. Biomarkers from blood or tissue can help predict treatment response and guide these decisions in other cancer types, but currently, no biomarkers exist for pancreatic cancer.

“This endeavor is an example of applying AI technology to an unmet clinical need, and offers tremendous translational potential,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “It aligns perfectly with our goal of personalizing cancer treatment for our patients and improving outcomes for all.”

To develop the tool, investigators used a platform called Computational Histology Artificial Intelligence, or CHAI. CHAI analyzes images of microscope slides containing samples of tumor tissue, which are stained to highlight minute details of the cells. Almost all patients have these samples taken when their tumors are biopsied.

The team analyzed tissue characteristics in samples from 25,000 pancreatic cancer patients who had received one chemotherapy regimen or the other. The platform’s AI capabilities made it possible to analyze more than 30,000 different features of the tissue samples. Investigators then matched tissue characteristics to treatment response to create the predictive tool.

When they tested the tool on data from a large clinical trial using the two pancreatic cancer treatment regimens, they found that it was able to accurately predict each patient’s response to the treatment received.

“Unlike most biomarker tests, where you need an extra sample of tissue or blood, this test requires only a scanned image of the patient’s existing biopsy slide,” Hendifar said. “You just send the image electronically and quickly receive a result with the treatment preference. And you don’t just learn which treatment is preferred. You learn how much more effective it is likely to be.”

The tool needs to be further validated in patients undergoing treatment before it is ready for clinical use, but Hendifar said that with that validation it could eventually be applied to other solid tumor types. It could even compare the potential benefit of different types of therapy, such as radiation therapy versus surgery.

“If the chance that a particular treatment will benefit a patient is 50-50, which is quite common in cancer therapy, then this may serve as a powerful tool to aid physician and patient decision-making,” Hendifar said. “And we can train the digital tool not just to choose between two available treatments, but to choose between multiple available treatments.”

Additional Cedars-Sinai authors include Brent K. Larson, DO; Vladimir Kazarov, MS; Natalie Moshayedi, BS; and Arsen Osipov, MD.

Other authors include Viswesh Krishna, BS; Vrishab Krishna, BS; Haochen Zhang, PhD; Katelyn Smith, BA; Kawther Abdilleh, PhD; Snehal Sonawane, MD; Akshay Neema, MS; Asit Tarsode, MS; Ekin Tiu, MS; Vivek Nimgaonkar, MD; Shawn Hutchinson, MSc; Daniela Bevacqua, BS; Sudheer Doss, PhD; Alejandra Alvarez, MS; Drew Watson, PhD, MBA; Waleed M. Abuzeid, MD; Barbara T. Grunwald, MD; Marcus Noel, MD; Rashmi Samdani, MD; Dove Keith, PhD; Rosalie C. Sears, PhD; Davendra Sohal, MD, MPH; Christos Fountzilas, MD; Grainne M. O’Kane, MD; Robert C. Grant, MD, PhD; Eric A. Collisson, MD; Lesli A. Kiedrowski, MS, MPH; Trevor J. Royce, MD, MS, MPH; Anirudh R. Joshi, MS; Aatur D. Singhi, MD, PhD; and Jennifer J. Knox, MD, MSc.

Funding: Supported in part by the Pancreatic Cancer Action Network (PanCAN - Know Your Tumor), the University Health Network, Toronto (COMPASS trial), and Valar Labs, Inc.

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The study, published in the journal Liver Cancer, found that these patients had overall survival rates that were 85% higher than patients who received immunotherapy alone.

“The data we reviewed showed that patients who received follow-up transplants or tumor removal after immunotherapy reduced the size of their tumors lived much longer than patients who just remained on immunotherapy,” said Ju Dong Yang, MD, medical director of the Liver Cancer Program at Cedars-Sinai and senior author of the study.

Liver cancer is rarely detected in the earliest stages, when tumors are small enough that a transplant or removal is possible. In advanced liver cancer, immunotherapy—medications that harness the power of a patient’s immune system—can shrink tumors but not cure the disease.

Previous research, also led by Cedars-Sinai, found that liver transplant or tumor removal is possible after immunotherapy shrinks a tumor to “downstage” the cancer. In this new study investigators wanted to see how well patients treated with these follow-up procedures fared.

They reviewed data on more than 4,300 patients with advanced liver cancer from the National Cancer Database, which contains more than 70% of all newly diagnosed cancer cases in the U.S.

Despite the higher overall survival rates after follow-up procedures, only about 3% of patients on immunotherapy went on to receive transplants or tumor removal. Most of those patients were treated at academic medical centers like Cedars-Sinai, the investigators found.

“Performing liver transplant following immunotherapy isn’t yet common practice,” Yang said. “This is unfortunate, as patients with advanced liver cancer often die without such treatment—even if their cancer is under control—because they also have other liver ailments. A transplant leaves the patient with a healthy liver.”

Yang plans to further make his case for more aggressive treatment for these patients through a new study that will launch in the coming months. Investigators will enroll patients who receive immunotherapy followed by liver transplants and will record their outcomes.

“When our physician-scientists create studies based on patient needs and then apply their findings to patient care, it improves outcomes for everyone we serve and for patients around the world,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “As an academic medical center, that is our mission.”

Additional Cedars-Sinai authors include Gwang Hyeon Choi, Hyun-Seok Kim, Michael Luu, Alexander Kuo, Walid S. Ayoub, Hirsh Trivedi, Yun Wang, Aarshi Vipani, Pin-Jung Chen, Steven A. Miles, Emily A. Kaymen, Andrew Hendifar, Tsuyoshi Todo, Todd V. Brennan, Georgios Voidonikolas, Steven A. Wisel, Justin Steggerda, Cristina Ferrone, Kambiz Kosari and Nicholas Nissen.

Other authors include Neehar D. Parikh and Amit G. Singal.

Funding: Dr. Singal’s research is supported by NCI R01 MD012565 and R01 CA256977. Dr. Yang’s research is supported by NCI K08CA259534.

Conflict of interest: Ju Dong Yang provides consulting service for AstraZeneca, Eisai, Exact Sciences, Exelixis, and Fujifilm Medical Sciences.

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Ruppin comes to Cedars-Sinai from the National Cancer Institute, where he was founding chief of the Cancer Data Science Lab.

“We are delighted to welcome Dr. Ruppin to Cedars-Sinai as a prestigious senior scientist enriching our cancer discovery programs,” said Shlomo Melmed, MB, ChB, executive vice president of Medicine and Health Sciences and dean of the Medical Faculty. “We continue to recruit the highest-quality faculty dedicated to translational research and advancing leading-edge cancer diagnosis and care.”

The Translational Research Institute will support Ruppin’s endeavors and offer what Ruppin calls a “golden opportunity” to work with the diverse patient populations served by Cedars-Sinai Cancer. His goal is to test, in clinical trials, the methods he has been developing.

“The Translational Research Institute is committed to establishing Cedars-Sinai as a global leader in translating scientific discoveries into life-changing patient care, and Dr. Ruppin’s work dovetails perfectly with this mission,” said Ze’ev Ronai, PhD, professor of Surgery and Biomedical Sciences and director of the institute.

Ruppin is developing artificial intelligence-based approaches to match patients to the best treatments in a personalized manner, which may complement existing approaches that identify molecular alterations in tumor cells. Currently, many cancer patients do not have their tumors sequenced in-depth because the process is expensive, available only at major academic medical centers and takes several weeks—which can cause treatment delays.

Ruppin’s approach, which will complement traditional laboratory techniques, uses digital images of tumor histopathology slides, thin slices of tumor tissue routinely obtained from patient samples so they can be examined beneath a microscope.

“We have discovered that by applying AI prediction tools to these slides, which have been the backbone of cancer diagnosis for 100 years, we can infer key parts of the molecular information that could be yielded by traditional sequencing—but without the associated time or expense,” Ruppin said.

Ruppin’s lab has successfully validated this approach in breast cancer, comparing molecular data from patients whose tumors have been sequenced in the traditional way with the tumor data inferred by his computational tools, and is now studying its application in other cancer types.

“Collaboration and translational science are central to improving patient outcomes,” said Cristina R. Ferrone, MD, chair of the Jim and Eleanor Randall Department of Surgery. “We must attack cancer in a multidimensional way and Dr. Ruppin’s expertise in deep-learning approaches adds another dimension to our arsenal.”

Ruppin earned his medical degree and a PhD in computer science from Tel Aviv University, where he served as a professor of Computer Science and Medicine. He has also served as a professor of Computer Science and director of the Center for Bioinformatics and Computational Biology at the University of Maryland, before moving to the National Institutes of Health.

A fellow of the International Society for Computational Biology, he received an NCI Director’s Award for his work on precision oncology in 2022, the DeLano Award for Computational Biosciences from the American Society for Biochemistry and Molecular Biology in 2023, and an NIH Director’s Award for developing new computational paradigms for precision oncology in 2024.

“Cedars-Sinai Cancer has a longstanding commitment to bringing precision oncology to as many patients as possible—here and around the world,” said Robert Figlin, MD, interim chair of Cedars-Sinai Cancer. “We’re proud to have Dr. Ruppin join us and to support his work.”

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The combination therapy, which adds a drug called enzalutamide to commonly prescribed hormone therapy, reduced deaths in patients with recurrent prostate cancer after surgery or radiation for whom other treatments are no longer an option. The trial results were published in The New England Journal of Medicine (NEJM) with simultaneous presentation during the European Society for Medical Oncology Congress (ESMO) Oct. 19 in Berlin.

“After initial treatment, some patients see their prostate cancer come back in an aggressive way and are at risk for their disease to spread quickly,” said Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer and co-principal investigator of the study. “Hormone therapy, which is what we’ve been offering patients for 30 years, has not improved survival and neither has anything else. That makes these findings a real game changer.”

The trial included more than 1,000 patients from 244 sites in 17 countries. All the patients were diagnosed with what is known as high-risk biochemically recurrent prostate cancer. Following the patients’ surgery or radiation therapy, the levels of prostate specific antigen, or PSA, in their blood had risen rapidly. PSA is a protein used to detect prostate cancer, and a rapid rise in PSA levels after treatment indicates a patient’s cancer is likely to return and spread—often to the bones or spine.

“We know these patients are at high risk of developing metastatic disease and dying of their cancer unless we offer a meaningful treatment option,” said Freedland, professor of Urology and the Warschaw, Robertson, Law Families Chair in Prostate Cancer.

Patients were randomly selected to receive standard hormone therapy alone, enzalutamide alone, or a combination of the two. After eight years, the risk of death was 40.3% lower in the combination group than in the other two groups, Freedland said.

“This clinical trial, one of many that Cedars-Sinai Cancer has offered to its patients, is an example of the translational work being done by our physician-scientists,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “The result will be improved treatment and better outcomes for patients everywhere.”

Freedland noted that, based on previous results published by the team, enzalutamide is approved by the Food and Drug Administration and listed in National Comprehensive Cancer Network treatment guidelines. These latest results, he said, are likely to strengthen the network’s recommendation and solidify this drug combination as the standard of care for patients with high-risk biochemically recurrent prostate cancer.

“These important findings identify a treatment that prolongs survival in men with aggressive prostate cancer,” said Hyung Kim, MD, a urologic oncologist and chair of the Department of Urology at Cedars-Sinai.  “The latest analysis complements previous studies that found enzalutamide significantly improved survival in other prostate cancer settings, and will change how we take care of our patients.”

Additional authors include Neal D. Shore, M.D.; Murilo de Almeida Luz, M.D.; Ugo De Giorgi, M.D., Ph.D.; Martin Gleave, M.D.; Geoffrey T. Gotto, M.D., M.P.H.; Christopher M. Pieczonka, M.D.; Gabriel P. Haas, M.D.; Choung-Soo Kim, M.D.; Miguel Ramirez-Backhaus, M.D.; Antti Rannikko, M.D., Ph.D.; Matko Kalac, M.D., Ph.D.; Swetha Sridharan, M.B.B.S.; Matt Rosales, Ph.D.; Yiyun Tang, Ph.D.; Ronald F. Tutrone Jr, M.D.; Balaji Venugopal, M.B.B.S., M.D.; Arnauld Villers, M.D., Ph.D.; Henry H. Woo, M.B.B.S., D.Med.Sc.; and Fong Wang, M.D., Ph.D.

Funding: The study was sponsored by Pfizer Inc. and Astellas Pharma Inc., the co‑developers of enzalutamide.

Disclosures: Stephen J. Freedland reports being a consultant to Astellas Pharma Inc., AstraZeneca, Bayer, Eli Lilly, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck, Novartis, Pfizer Inc., Sanofi, Sumitomo Pharma America, Inc. (formerly Myovant Sciences, Inc.), and Tolmar.

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.

“Staging helps clinicians answer two questions,” said Allen Ho, MD, professor of Surgery, director of the Head and Neck Cancer Program at Cedars-Sinai and lead author of the study. “The first: How serious is the cancer? The second: What is the best treatment?”

Previous staging guidelines for HPV-positive throat cancer were so broad that as many as 80% of patients were classified as stage 1, with three different possible treatment strategies. Some stage 1 patients were treated with surgery alone, some with surgery plus radiation therapy, and some with surgery and radiation plus chemotherapy.

“The new staging will better inform clinicians and patients about a patient’s prognosis and will minimize inconsistencies in the treatments patients are offered,” Ho said. “Currently, a patient diagnosed as stage 1 might be offered surgery plus radiation and chemotherapy, while another stage 1 patient may be offered surgery alone. The new guidelines will help ensure each patient receives the most appropriate treatment.”

Investigators divided the huge group of stage 1 patients into three separate groups, Ho said. They created new subdivisions of nodal staging, which consider whether cancer has spread to lymph nodes, and paired a more cohesive treatment recommendation with each.

“Perhaps the biggest change in the new staging system is that it takes into account something called extranodal extension, where the cancer has not only spread to the lymph nodes, but has progressed further to destroy the lymph node capsule and spill into the surrounding tissue. Inclusion of this factor is important, because it often changes both prognosis and the recommended treatment following surgery,” said Zachary Zumsteg, MD, professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai and senior author of the paper. 

Ho noted that cases of HPV-positive throat cancer, caused by the same virus that causes cervical cancer, have outpaced cervical cancer because women are routinely screened for cervical cancer. They are also more likely than men to receive the HPV vaccine, which can prevent both cancer types.

The new guidelines were developed by an international committee led by Ho that analyzed data on more than 14,000 patients from 984 healthcare facilities. They are set to become the official worldwide staging guidance in the coming year.

“These findings represent compelling evidence for staging modification,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer and the Steven Spielberg Family Chair in Hematology Oncology. “It is a challenging endeavor, but it improves the information and care that we are able to offer our patients; Cedars-Sinai Cancer is honored to be part of this international effort.”

Ho suggested that patients with newly diagnosed HPV-positive throat cancer ask their care team how these new guidelines have shaped their staging and treatment options.

“Patients should ask their caregivers how these new guidelines impact the clinician’s thinking about the patient’s staging, prognosis and which treatment to offer,” Ho said.

Additional Cedars-Sinai authors include Brian O’Sullivan.

Additional authors include Shao Hui Huang, Michael Luu, Mererid Evans, Robert L. Ferris, James S. Lewis Jr., Raja R. Seethala, Sue S. Yom, Hisham Mehanna, Barton F. Branstetter, Nabil F. Saba, Snehal G. Patel, and William M. Lydiatt.

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The Y chromosome is one of two chromosomes that determine biological sex in mammals. Females have two X chromosomes, males have one X and one Y chromosome, and it is common for males to lose the Y chromosome in some of their cells as they age.

Cedars-Sinai research published in 2023 found that loss of the Y chromosome in bladder cancer cells in men helped those cells evade the body’s immune system, allowing the cancer to grow. However, tumors with loss of the Y chromosome also were more susceptible than those with an intact Y chromosome to immune checkpoint therapy.

Given the previous findings, that Y chromosome loss in cancer cells was problematic in most male tumors, study co-senior authors Simon Knott, PhD, assistant professor of Biomedical Sciences at Cedars-Sinai, and Dan Theodorescu, MD, PhD, wanted to investigate the consequences of Y chromosome loss in males with other types of cancer, Knott said. 

Using large publicly available datasets, the new study examined loss of the Y chromosome in cancer cells from a range of cancers. Unexpectedly, the investigators found that many other cell types associated with tumors also had Y chromosome loss, prompting further investigations, Knott said.

“When we started to investigate Y loss in other cells in the tumor, our jaws dropped because the link between loss of the Y chromosome in cancer cells and in immune cells from the same tumor was so striking,” Knott said. “Our work showed that if cancer cells lost the Y chromosome, it was very likely immune cells would also have lost the Y chromosome. Losing the Y chromosome in both these cell types at once correlated with hyperaggressive cancer cells and malfunctioning immune cells that are meant to attack the cancer cells. This creates an aggressive tumor with very poor outcomes.”

In addition to the cancer databases, investigators confirmed their findings by looking at loss of Y in patient tumor samples and in preclinical studies using additional techniques to measure Y chromosome loss, which confirmed their findings.

The findings could also have implications for patients receiving T-cell therapies, where immune cells called T-cells are harvested from a patient, altered in the lab so that they are more effective in fighting cancer, then delivered back to the patient.

“Our findings suggest that screening for loss of the Y chromosome in those T-cells or any product generated from them before being given back to a patient could be extremely important,” Knott said. “We predict that cellular therapies with T-cells lacking the Y chromosome will be significantly less effective than those with an intact Y chromosome.”

Further research is needed to help investigators understand how best to adapt these therapies to account for loss of Y.

“Given that a high percentage of older, healthy men experience loss of the Y chromosome in at least some of their cells, these findings could affect many cancer patients,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer and professor of Medicine and Biomedical Sciences. “Continued investigation into how to translate these findings to more effective therapies fits well with our focus on precision medicine as a way to improve patient outcomes.”

Additional Cedars-Sinai authors include Xingyu Chen, currently at Johns Hopkins University; Yiling Shen; Suhyeon Choi; Mukta Basu; Lena Hoelzen; Martina Tufano; Hany A. Abdel-Hafiz; Saravana Kumar Kailasam Mani; Maryam Ranjpour; Jiani Zhu; V. Krishnan Ramanujan; Ekaterina K. Koltsova; Vinicius Calsavara; and Dan Theodorescu, currently at the University of Arizona.

Funding: This work was supported in part by NIH grant CA278732.

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“Colorectal cancers frequently have specific mutated genes, some of which can be targeted with existing targeted therapies,” said Jane Figueiredo, PhD, professor of Medicine and co-leader of the Cancer Prevention and Control Program at Cedars-Sinai Cancer and co-senior author of the study. “We identified distinct molecular alterations of colorectal tumors that are more likely to occur in some patients based on their genetic ancestry. These results could help us target treatments and better understand differences in treatment response among different patient groups.”

Figueiredo said that molecularly driven therapies for colorectal cancer are rapidly expanding, can already target at least six distinct tumor compositions, and that further studies are needed to identify therapies to target the distinct features identified in this research.

Additional Cedars-Sinai authors include Jun Gong, Nathalie T. Nguyen and Nicole C. Loroña.

Additional authors including Marco Matejcic, Jamie K. Teer, Hannah J. Hoehn, Diana B. Diaz, Kritika Shankar, Domenico Coppola, Clifton G. Fulmer, Ozlen Saglam, Kun Jiang, W. Douglas Cress, Teresita Muñoz-Antonia, Idhaliz Flores, Edna R. Gordián, José A. Oliveras Torres, Seth I. Felder, Julian Sanchez, Jason B. Fleming, Erin M. Siegel, Jennifer A. Freedman, Julie Dutil, Mariana C. Stern, Brooke L. Fridley, and Stephanie L. Schmit.

Cancer Research study funding: Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under award numbers R01CA238087, R01CA155101, U54CA163068, U54CA163071, U54CA233465, U2CCA252971, P30CA014089, R01CA284732, R01CA248931, P20CA252733, and P50CA285275. It was further supported by a Moffitt Cancer Center Team Science Award. This research was also made possible through the Total Cancer Care Protocol and by the Tissue, Collaborative Data Service, Molecular Genomics, and Biostatistics and Bioinformatics Shared Resources at the H. Lee Moffitt Cancer Center & Research Institute; an NCI-designated Comprehensive Cancer Center (P30CA076292). Sequencing data was based in part upon data generated by the Oncology Research Information Exchange Network (ORIEN; http://www.oriencancer.org/) and support and coordination by Aster Insights (formerly M2Gen; https://www.asterinsights.com/).

“One of the most challenging tumors to treat is cancer that has spread to the brain,” said Lali Medina-Kauwe, PhD, associate director of Basic Research at Cedars-Sinai Cancer, professor of Biomedical Sciences, and senior author of the study. “Our findings show that our tumor-invading protein can deliver a potent payload of therapy directly to these tumors. It is like a cancer smart bomb.”

A challenge in delivering chemotherapy to brain tumors has been the blood-brain barrier, which stops harmful particles from traveling from the bloodstream to the brain but also blocks therapeutic agents. Medina-Kauwe and team found that a protein called HER3 is present on the blood-brain barrier, and that it helps their tumor-invading protein cross from the bloodstream to the brain.

The investigators conducted experiments using a unique blood-brain barrier “organ chip.” In this laboratory device, small groups of induced pluripotent stem cells are transformed into blood vessel cells and brain cells and put in compartments in a pattern that mimics what happens in the human brain.

When investigators flowed their protein through the blood vessel portion of the chip, they saw that it crossed over and accumulated in the brain matter, Medina-Kauwe said. And when they blocked HER3 proteins in the chip, tumor-invading proteins did not cross over, which suggests that HER3 aids their passage from the bloodstream into the brain.

“These blood-brain barrier organ chips are the next best thing to experiments in humans,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and a co-author of the study. “They allow us to create the ideal conditions for testing therapies such as this one. We can even use the patient’s own stem cells and make personalized organ chips to test how the drug may work for each person.”

The HER3 protein is also present on the surface of many types of cancer cells—especially in tumors that have spread from another part of the body to the brain. And the investigators’ experiments in laboratory mice showed that tumor-invading proteins directly targeted these HER3-positive tumors, reducing their growth without accumulating in other organs.

“Most cancer drugs enter healthy cells as well as cancerous cells, causing major side effects, but this tumor-invading protein selectively enters tumor cells and spares the healthy cells,” said study co-author Ravinder Abrol, PhD, associate professor of Chemistry and Biochemistry at California State University, Northridge (CSUN), and member of the Cancer Biology Program at Cedars-Sinai. “Our ability to actively target tumor cells is a major step toward cancer therapies with reduced toxicity and enhanced safety profiles.”

Once the protein enters tumor cells, a unique feature allows it to evade their defenses.

“Most cells, including tumor cells, encapsulate invading particles in a bubble that allows the cell to harmlessly digest them,” Medina-Kauwe said. “Our tumor-invading protein includes a pinwheel-like structure that prevents digestion. When our protein enters the unique environment of the tumor cell, it opens this pinwheel and breaks out of the bubble. When we pair the protein with chemotherapy, it can deliver a lethal blow.”  

Medina-Kauwe said the findings are promising and are a step toward developing therapies that can deliver treatment to advanced tumors that currently have no other clinical option.

“We are finding that more and more tumor types—including breast, lung and colorectal tumors, and metastatic melanoma, as well as many primary brain tumors—are HER3 positive,” Medina-Kauwe said. “We’re looking forward to pursuing further studies to determine whether we can develop treatments for these tumor types.”

Additional Cedars-Sinai Authors: Felix Alonso-Valenteen, Simoun Mikhael, HongQiang Wang, Jessica Sims, Michael Taguiam, James Teh, Sam Sances, Michelle Wong, Tianxin Miao, Dustin Srinivas, Nelyda Gonzalez-Almeyda, Ryan H. Cho, Kimngan Nguyenle, Erik Serrano, Briana Ondatje, Rebecca L. Benhaghnazar, John Yu, Clive N. Svendsen, Ravinder Abrol

Additional Authors: Romny Sanchez, Harry B. Gray, Zeev Gross

Funding: This research was supported by grants from the National Institutes of Health (NIH) [NCI R01 CA258204, R01 CA270324, and NCATS UL1 TR001881 core vouchers V002, V087, and V176 to L.M.K]; and the Department of Defense (DoD) [BCRP W81XWH-15-1-0604, W81XWH1910592 to L.M.K and R.A.]. F.A.V. was supported in part by a training grant from the National Institutes of Health [T32 HL134637]. B.O. and S.S. were supported by National Institutes of Health (NIH) UG3NS105703.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

, a prominent cancer investigator and director of the Translational Research Institute at Cedars-Sinai, has received an Outstanding Investigator Award from the National Cancer Institute. This is the second time that Ronai has collected the award, which supports cancer researchers working on biomedical, clinical and behavioral innovations and discoveries.

The award, recognizing both past achievements and the promise of future work, comes with approximately $4.2 million over seven years to support Ronai’s continuing work to study how melanoma cells evade cancer therapies and the body’s immune system.

“Imagine the cancer as the navigation system in your car,” Ronai said. “We expect it to take the main highway, where we have therapies that can stop it from spreading. But instead, it finds side roads so that it can evade those therapies and metastasize. Melanoma is especially prone to spreading, and our biggest challenge in treating patients with this cancer is metastasis. We are working to find the side roads the disease is using so we can stop this spread and improve patient survival.”

Recently, Ronai has been studying rewired signaling in melanoma cells, and this will be much of his focus for the duration of the award. This rewired signaling, which has gone awry in cancer cells, interferes with the breakdown of old, damaged or abnormal cell components as well as the normal process of cell death.

“These rewired signals make cancer cells behave differently than normal cells would,” Ronai said. “The cells do not die; instead they survive therapies. One of the key components that our work will focus on is the role of these abnormal signals in life and death of cancer cells.”

In carrying out his work, Ronai plans to take full advantage of the unique cross talk that exists between clinicians and investigators at Cedars-Sinai.

“This cross talk allows close collaboration that benefits all parties engaged in cancer research,” Ronai said. “When I speak with Cedars-Sinai clinicians, I see that the ‘bench-to-bedside-and-back’ concept has truly come to fruition here.”

Shlomo Melmed, MB, ChB, executive vice president of Medicine and Health Sciences and dean of the Medical Faculty, said that teamwork between investigators and clinicians is essential to forging new paths in cancer prevention, treatment and precision medicine.

“This well-deserved award recognizes the value of Dr. Ronai’s outstanding research productivity and how well it dovetails with our mission to advance cancer care and improve outcomes for our patients,” Melmed said. “We look forward to the discoveries and innovations that are sure to ensue from these efforts.”

Ronai, who during his career has collaborated with investigators and clinicians across the country and internationally, believes that his work will have implications beyond melanoma.

“Over the past decade we have made important contributions to advance our understanding and treatment of prostate, breast and pancreatic cancer. I expect the work we do in the next few years will similarly lead to advances against a variety of cancer types,” Ronai said. “My hope is to redefine the future of therapy based on our discoveries.”

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

“One of our key findings was that even in a setting such as the VA where patients have equal access to care, Black patients have a much higher burden from prostate cancer than white patients do,” said Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer and senior author of the study, who holds a joint appointment as staff physician at the Durham VA Medical Center. “Our findings also point to important racial differences in risk that a patient’s cancer will progress. This information will help spotlight areas for further investigation so that we can identify ways to help reduce the excess burden and death from prostate cancer among Black patients.”

Additional Authors: Shannon R. Stock, PhD; Michael T. Burns, BA; Justin Waller, MS; Amanda M. De Hoedt, MS; Joshua A. Parrish, BS; Sameer Ghate, PhD; Jeri Kim, MD; Irene M. Shui, PhD

Funding: This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc.

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The research was published in the peer-reviewed journal The Lancet Diabetes & Endocrinology.

“Many studies have established that the incidence of thyroid cancer has dramatically increased for at least four decades, but the probability of dying of thyroid cancer has remained exactly the same,” said Zachary Zumsteg, MD, associate professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai Cancer and senior author of the study. “This means we are diagnosing and treating many cancers that would do no harm despite recent efforts to reduce overdiagnosis.”

Cancer of the thyroid, a hormone-secreting gland at the front of the neck, is treated surgically. All surgeries have risk, and removing the thyroid often requires patients to take hormone supplements for life, Zumsteg said.

Investigators analyzed data from more than 91,000 thyroid cancer patients registered in public databases from 1975 to 2019 to determine trends in thyroid cancer incidence according to year of birth and year of diagnosis.

A plateau: Zumsteg said efforts have been made to curb overdiagnosis of thyroid cancer over the past several decades, and previous research suggested that rates of thyroid cancer were finally beginning to decline in recent years.

“When we looked at a broader range of data, we found there has been no decline in thyroid cancer diagnoses,” Zumsteg said. “Rates have hit a plateau, with no further increases over the past decade or so. However, the plateau is at peak levels. We continue to diagnose many patients who will not benefit from surgery, and we have essentially made no progress in reducing unnecessary treatments.”

Increased medical imaging over time: Investigators found that the main factor linked with increased thyroid cancer incidence appears to be the passage of time. They theorized that this is mainly due to increased detection of thyroid nodules in modern medical practice.

“People visiting the doctor in 1975 were less likely to receive imaging than those visiting the doctor in 2019,” Zumsteg said. “So today doctors are finding thyroid nodules that would not have been detected in previous decades, leading to more biopsies and diagnoses of small, slow-growing thyroid cancers that might not require treatment.”

A bump in middle age: The study also found that thyroid cancer incidence has increased disproportionately in middle-aged individuals, who are more likely to interact with the medical system.

“Our analysis found that in 1975, the probability of being diagnosed with thyroid cancer was basically the same in people of all ages,” Zumsteg said. “Over time, the increase has been concentrated in women ages 40-69 and men ages 50-79. This especially affected women, who tend to interface with the medical system more often than men.”

Zumsteg said that thyroid cancer overdiagnosis could be addressed with a two-pronged approach. Raising the threshold for both imaging and biopsy of thyroid nodules would reduce overdiagnosis. Less aggressive management would further reduce thyroid cancer overtreatment.

A practice called “active surveillance,” where doctors monitor thyroid cancer patients with regular imaging and perform surgery only if the cancer appears to be growing, could help. There are several ongoing clinical trials of active surveillance, including one at Cedars-Sinai.

“The hope is that these trials will make clinicians and patients more comfortable with active surveillance and that updated clinical guidelines will bring the practice into widespread use,” said study co-author Allen Ho, MD, co-director of the Thyroid Cancer Program and professor of Surgery at Cedars-Sinai, and leader of the Cedars-Sinai clinical trial. “If current trends continue, we will continue to overdiagnose thyroid cancer and to needlessly treat patients—doing more harm than good.”

Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair, said that research such as this is an important part of a community-based approach to cancer prevention and treatment.

“Through our office of Community Outreach and Engagement we promote preventive screening throughout the communities that we serve,” Theodorescu said. “And through our research, we are working to ensure that when we offer treatment, it will yield the best possible outcomes for patients.”

Additional Cedars-Sinai authors: Michael Luu, MPH; Wendy L. Sacks, MD; Jon Mallen-St. Clair, MD, PhD

Additional authors: Michelle M. Chen, MD, MHS; Lisa Orloff, MD; Lauren P. Wallner, PhD, MPH; Susan C. Pitt, MD, MPHS

Read more on the Cedars-Sinai Blog: Active Surveillance for Thyroid Cancer

The study, published in the peer-reviewed journal Science Advances, could improve the effectiveness of the widely used platinum-based medication and reduce the required dosage, minimizing side effects.

“We found that by inhibiting the action of a gene that limits the importation of the drug into tumor cells, we can increase the uptake of cisplatin and thus its effectiveness,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, the PHASE ONE Foundation Distinguished Chair, and co-senior author of the study. “This gives us a druggable target to enhance patient response, especially in cases of advanced disease, and we have demonstrated this in multiple cancer types. We hope these findings will make cisplatin therapy more effective and an option for more patients.”

Cisplatin is widely used as part of first-line therapy for many cancer types, including bladder, ovarian, cervical, testicular, lung, and breast cancer, as well as sarcomas, lymphomas, and leukemias. Nearly 50% of all patients who receive chemotherapy receive platinum-based drugs, which work by damaging the DNA of tumor cells to prevent them from multiplying. However, tumor cells are often able to “escape” the drugs’ effects, so these therapies rarely cure advanced disease.

To explore ways to overcome cancer cells’ resistance to cisplatin, investigators from Cedars-Sinai, the University of Colorado Anschutz Medical Campus, and Erasmus University Medical Center, Rotterdam, The Netherlands, worked with bladder cancer cells in laboratory mice and in cell culture, and also with organoids grown from patients’ bladder cancer cells. Tumor organoids are clusters of cells, grown in a petri dish, that share many characteristics with actual tumors.

“We showed that inhibition of a gene called NPEPPS increased sensitivity to cisplatin in these cells and organoids, providing the first description of this gene’s role in cisplatin resistance,” Theodorescu said. “Our data have shown the importance of this pathway in various cancer types and in patients who had platinum-based therapy. Our data have clearly identified NPEPPS as a promising target for drug development for patients with treatment-resistant cancer.”

Previous research has shown that platinum-based chemotherapy used along with immunotherapy can improve immunotherapy effectiveness, which further broadens the impact of these findings, Theodorescu said.

“All cells have channels that sit on the cell surface and control what goes in and out of the cell. It turns out that some of these channels import platinum drugs into cells,” said James Costello, PhD, associate professor of Pharmacology at University of Colorado Anschutz Medical Campus and co-senior author of the study. “What we discovered in this study is that NPEPPS is the protein that gets turned up in response to platinum drugs and it blocks the channels that import platinum drugs. So, by targeting NPEPPS therapeutically, we can prevent it from blocking these channels. We are continuing to study how blocking NPEPPS therapeutically affects both tumor and normal cells, including interactions with the immune system.”

Ongoing studies are aimed at more fully understanding how NPEPPS inhibits the import of cisplatin into cancer cells and at discovering drugs that can inhibit NPEPPS. Combining these drugs with cisplatin would make the cisplatin more effective at killing cancer cells, leading to better patient outcomes.

Additional Cedars-Sinai authors: Saswat Mohapatra, Fangyuan Qu, Corazon Gutierrez, Huihui Ye, Sarah Parker

Additional authors: Lily Elizabeth R Feldman, Robert T Jones, Charlene B Tilton, Michael V Orman, Molishree Joshi, Cailin S Deiter, Eric T Clambey, James C Costello, Mathijs Scholtes, Tokameh Mahmoudi, Tahlita Zuiverloon, Travis P Broneske

Funding: Anschutz Foundation to J.C.C., CA268055 to J.C.C. and D.T., Pharmacology T32 Training Grant GM007635 supported L.E.F., Cancer Center Shared Resources, NIH NCI CA046934

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

“The incidence of pancreatic cancer among the Black population is at least 50% higher than the incidence of other racial groups. Furthermore, research has shown that Black patients have the lowest survival rate,” said Debiao Li, PhD, director of the Biomedical Imaging Research Institute and professor of Biomedical Sciences and Imaging at Cedars-Sinai, and co-principal investigator of the study. “We know that there are genetic, socioeconomic and lifestyle differences between ethnic and racial populations, and we suspect some of these differences might affect pancreatic tissue and pancreatic cancer risk.”

Li and co-investigators received a grant from the National Cancer Institute in 2022 and developed a tool that uses CT scans and AI to detect minute changes in the pancreas, which is part of the digestive system. These changes can indicate a patient is likely to develop pancreatic cancer years before they develop the disease, thus enabling an earlier diagnosis when treatments are most effective. This investigative team has received a new grant to conduct a pilot study that will allow them to determine whether those characteristics differ in Black patients.

The team will collaborate with Cemal Yazici, MD, associate professor of Medicine at the University of Illinois Chicago, which, like Cedars-Sinai, serves a large population of Black patients.

Predictive models for pancreatic cancer based on symptoms, genetics and weight haven’t been shown to be accurate on their own, said Stephen Pandol, MD, director of Basic and Translational Pancreas Research at Cedars-Sinai and co-principal investigator of the study. Meanwhile, blood and urine tests for pancreas cancer are still in development.

“Packaging these tests with our imaging tool could eventually prove effective in predicting who will develop pancreatic cancer,” Pandol said. “Our goal is to perfect our tool, then apply it to a population to see if we can diagnose individuals earlier.”

Pancreatic cancer is one of the deadliest cancers, with only around 10% of patients surviving five years after diagnosis. Early detection and surgical intervention can increase five-year survival rates to more than 50%, but this is rare because early pancreatic cancer causes few symptoms.

“Drilling down to understand cancer risk at precision levels is key to the Cedars-Sinai Cancer mission to bring personalized cancer care to every patient,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. "This work in early detection nicely complements recent work showing that a new AI-based precision medicine approach called the Molecular Twin Precision Oncology Platform can predict outcomes of pancreatic cancer."

With the help of improved predictive tools, patients at the highest risk can be monitored via annual imaging so any cancer that develops is detected at the earliest stage.

“If we can diagnose a patient’s pancreatic cancer two or three years earlier, that could make a life-and-death difference,” Li said.

Read more on the Cedars-Sinai Blog: Pancreatic Cancer Clinic Saves Time and Lives

Their achievement, described in the peer-reviewed journal Nature Communications, significantly expands AI’s healthcare applications. 

The new AI method, also called a model, offers a much-needed alternative to tumor registries, the databases maintained by governments and hospitals. Researchers normally use tumor registries to screen cancer patients for clinical trials. Cancer registries require specially trained employees to manually identify a patient’s cancer stage by reviewing laboratory reports, clinicians’ notes and other information. The process can be slow and tedious.

“By the time a cancer patient’s data is entered into a tumor registry, months may have passed, along with the opportunity for the patient to participate in relevant clinical trials or other treatments,” said Nicholas Tatonetti, PhD, vice chair of Computational Biomedicine at Cedars-Sinai, associate director for Computational Oncology at Cedars-Sinai Cancer and corresponding author of the study. “Our AI model can dramatically reduce that delay, accelerating the pace of research and expanding patients’ access to clinical trials.”

The team’s AI model quickly identifies the cancer stage by extracting and interpreting the text of just one element of a patient’s electronic health record: the pathology report, which describes the findings of pathologists examining tissue specimens from the patient. In tests involving thousands of patient records, the study’s investigators confirmed that the AI model they created was highly effective in staging patients’ cancers.

The method is based on a so-called transformer model of AI, which is designed to simulate the complex decision-making power of the human brain. The study team first “trained” the model to stage cancers using publicly available pathology reports from a government database, The Cancer Genome Atlas. These reports covered nearly 7,000 patients and included 23 types of cancers.

To make sure the model worked in various settings, investigators then applied it to nearly 8,000 pathology reports maintained by a single medical center. The results, as measured by a standard statistic for evaluating AI models, rated the method as highly accurate. “This was an important finding because it means that our AI model is an ‘off- the-shelf’ tool that can be generalized to other institutions without requiring that it be trained for each location,” Tatonetti said.

Besides screening patients by their cancer stages for clinical trials, the AI model also can be used to automate classification of patients for observational and retrospective data analysis, and for potential treatments, according to Tatonetti. “Future research could build on our method to integrate the pathology text with other types of clinical data, potentially advancing personalized cancer treatment,” he said.

The creation of the AI model was made possible by earlier research, also led by Tatonetti, that removed technical obstacles to computers extracting and analyzing pathologists’ notes from electronic health records.

In a notable decision, the investigators in the new study have made their AI model, which they named BB-TEN: Big Bird – TNM staging Extracted from Notes, available to other institutions for academic uses and certain other purposes.

“By speeding up the selection of candidates for cancer clinical trials, this innovative AI model shows promise for accelerating the development of relevant treatments and making them available to more patients,” said Jason Moore, PhD, chair of the Department of Computational Biomedicine at Cedars-Sinai.

Other Cedars-Sinai authors include Jacob Berkowitz, Jose M. Acitores Cortina and Kevin K. Tsang. An additional author was Jenna Kefeli.

Kefeli and Tatonetti were supported by award number R35GM131905 from the National Institute of General Medical Sciences of the National Institutes of Health.

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The research findings were published in the peer-reviewed journal JAMA Internal Medicine.

Prostate cancer is the second-most common cancer in the U.S., exceeded only by breast cancer. About one-eighth of U.S. men are diagnosed with prostate cancer at a median age of 67 according to the National Cancer Institute. Most patients have slow-growing, localized tumors, confined to the prostate gland, that are unlikely to threaten their lives. Instead of immediate treatment, these low-risk patients can be monitored through “active surveillance,” in which examinations and tests are performed on a regular schedule to make sure the disease is not progressing.

“Use of active surveillance has increased over the last 15 years for men with low-risk prostate cancer, and it is now the most common treatment for these men,” said Timothy Daskivich, MD, director of Urologic Oncology Research for the Cedars-Sinai Department of Urology and corresponding author of the new study. “This approach allows these patients to avoid the risks of urinary incontinence, erectile dysfunction and other potential side effects of surgery and radiation therapy.”

Conservative management, which includes active surveillance or watchful waiting, is also recommended for men with limited life expectancies who likely will not live long enough to benefit from aggressive local treatment, even for higher-risk cancers. However, for these men, the trend is going in the opposite direction, as measured by the investigators’ analysis of extensive data from the Veterans Affairs health system. They found that for men with limited life expectancies and intermediate- and high-risk cancers, conservative management was being employed less often and that more were receiving aggressive local treatment with surgery or radiation.

“We found this pattern surprising,” Daskivich said. “Prostate cancer patients with life expectancies of less than five or 10 years were being subjected to treatments that can take up to a decade to significantly improve their chances of surviving cancer, despite guidelines recommending against treatment.”

For their study, the investigators analyzed medical data on 243,928 men in the Veterans Affairs health system who were diagnosed with localized prostate cancer between 2000 and 2019.

Among patients with average life expectancies of less than 10 years, the proportion who underwent treatments such as surgery or radiation for low-risk prostate cancer rather than receiving active surveillance decreased from 37.4% to 14.7%; but treatment for intermediate-risk disease increased from 37.6% to 59.8%. Among patients with average life expectancies of less than five years, treatment for high-risk disease increased from 17.3% to 46.5%. Among men who were overtreated, roughly 80% were treated with radiation therapy.

Solving the issue of overtreatment in higher-risk prostate cancer patients with limited longevity requires a multifaceted approach involving better estimation, communication, and integration of life expectancy into decision-making, Daskivich said. He and his team have proposed a “trifecta” method for communicating cancer prognosis to the patient. This method involves the physician discussing the likelihood of dying from the cancer with treatment versus without treatment at the endpoint of the patient’s life expectancy. This approach personalizes the risk of the cancer that is relevant to each patient.

“Our goal is to encourage clinicians to make longevity part of the discussion about the best treatment options so that prostate cancer patients with limited life expectancies can make educated choices,” Daskivich said. “A patient may be given this data and choose to pursue surgery or radiation treatments regardless of a limited probability of benefit.  Another patient may take a different course.”

“Every individual is different, and statistical averages for lifespan, treatment effectiveness and cancer risk cannot predict outcomes with certainty,” Daskivich added. “But patients should be given the opportunity to make informed decisions with the best possible information.”

Hyung L. Kim, MD, chair of the Department of Urology at Cedars-Sinai, said the JAMA Internal Medicine study reflects a signature strength of Cedars-Sinai: the close cooperation among researchers and clinicians. “Many of our investigators are themselves clinicians, which ensures that their research addresses real-life problems in healthcare with an emphasis on finding solutions,” he said.

Other Cedars-Sinai authors include Michael Luu and John R. Heard. Other authors include I-Chun Thomas from Stanford University and senior author John T. Leppert from Stanford University in Stanford, California, and the VA Palo Alto Health Care System in Palo Alto, California.

This work was supported in part by VA Merit Review (I01 HX0021261 to JL). The Department of Veterans Affairs Health Services Research and Development Service work was supported using resources and facilities at the VA Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. Government.

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Numerous laboratory studies have shown that drug-radiotherapy combinations increase the effectiveness of cancer therapy, but clinical trials in humans have been less successful. Only one new non-chemotherapeutic drug has been approved by the Food and Drug Administration for concurrent treatment with radiation.

“One of the biggest reasons for this is that early-phase clinical trials investigating these combinations are challenging to design and implement,” said Zachary Zumsteg, MD, associate professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai and first author of the paper. “Since many side effects of radiotherapy occur after treatment is completed, it can take longer to determine the appropriate dose of treatment. Testing of drug-radiation therapy combinations often occurs in patients receiving first-line therapy, leading to less tolerance of unexpected side effects. And because radiotherapy affects each organ differently, new drug-radiotherapy combinations must be tested separately for cancers arising in different parts of the body.”

To address these challenges, investigators suggest designing trials that use mathematical models with real-time toxicity data to calculate appropriate doses for each patient, allowing for continuous patient enrollment and making trials more efficient. They also advocate testing multiple drug-radiotherapy combinations simultaneously to limit the number of patients receiving any specific drug-radiotherapy combination at a given time. They note that these trial designs require substantial infrastructure and expertise, making them best suited for implementation in large cooperative group clinical trial networks.

The authors suggest that if these clinical trial designs are widely adopted, they are more likely to lead to the development of additional safe and effective cancer treatments.

Additional authors: Siddharth Sheth, Salma K Jabbour, Krishnan R Patel, Randall J Kimple, Terence M Williams, Meng Xu-Welliver, Pedro A Torres-Saavedra, Arta M Monjazeb, Jyoti Mayadev, Steven E Finkelstein, John M Buatti, Sandip P Patel, Steven H Lin.

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A syndrome called cachexia, which triggers unexplained loss of weight and muscle mass, causes severe illness and death among patients with cancer and other serious health conditions.

November is a month designated for raising awareness about lung and pancreatic cancers, and Andrew Hendifar, MD, medical director of Pancreatic Cancer at Cedars-Sinai Cancer, sat down to talk with the Cedars-Sinai Newsroom about cancer cachexia. Hendifar is co-author of recent clinical trial results, published in The New England Journal of Medicine, that could yield the first Food and Drug Administration-approved medication for the condition.

Why is understanding cachexia so important?

More than 25% of cancer-related deaths can be attributed to cachexia. It affects 80% of patients with pancreatic cancer, and half of patients with advanced lung cancer. We also see it among patients with colon, kidney and stomach cancer, as well as heart, lung and kidney disease.

As many as 75% of patients with cancer have significant unexplained weight loss six months before they are diagnosed, but this clue is often missed. People just think the latest weight loss strategy they have tried is finally working. Unintentional weight loss is a significant health problem, and anyone who is losing weight unexpectedly should immediately seek the care of a health provider to investigate it further. It’s a huge problem and a huge unmet need. At this point, all we are really able to offer patients with cachexia is a referral to a dietitian.

What causes cachexia?

For decades we've been trying to figure out what causes cachexia and what we can do to treat it. After pursuing many different pathways, we recently made significant progress with a drug that targets the GDF-15/GFRAL pathway.

GDF-15, growth differentiation factor 15, is a hormone that is elevated in patients with cancer and certain other medical conditions, and in patients on certain types of chemotherapy. Its role in normal physiologic function is not yet fully understood. It seems to be associated with appetite and with stress, and there have been several attempts over the past few years to target GDF-15 with various therapies.

Tell us about the recent clinical trial.

The therapy we tested, a monthly injection that caused few side effects, blocks the action of GDF-15. Our Phase 2 clinical trial included patients with non-small cell lung, pancreatic and colorectal cancers. Patients taking this new drug had improved weight gain and physical activity as compared with patients receiving a placebo. Not only is this the first promising cachexia drug, it is also the first drug showing promise in blocking the action of GDF-15.

What will happen next with this drug?

Several new clinical trials should be opening soon at various institutions, targeting cachexia not only in patients with cancer, but in those with other diseases as well. Patients with cachexia should be referred to a dietitian and also work with a physical therapist to help recover muscle mass. And they can ask their health care provider about opportunities to participate in one of these clinical trials.

Have there been any other promising options for cachexia patients?

Cedars-Sinai was recently part of an international consortium that conducted a Phase 3 trial called the MENAC trial. This trial found that a combination of protein and omega 3 supplementation, dietary counseling, a home exercise program and ibuprofen improved weight by roughly 2 pounds. But this hasn’t yet become part of official guidelines for cachexia care.

Read more on the Cedars-Sinai Blog: The Link Between Pancreatic Cancer and Diabetes

“Cancer is the leading cause of death in most Asian American ethnic groups, a fact that has been understudied for years,” said Zul Surani, associate director of Community Outreach and Engagement at Cedars-Sinai Cancer and the Cancer Research Center for Health Equity at Cedars-Sinai. “Because of our continual work to build partnerships in the community, Cedars-Sinai is well positioned to contribute to this incredibly important undertaking.”

Cedars-Sinai is the largest single center enrolling participants into the national effort, which is funded by the National Cancer Institute and will include 20,000 people over the next four years. Asian Americans ages 30-75 who have not been diagnosed with cancer are eligible to participate.

“This study will look at traditional cancer risk factors such as lifestyle and environmental exposures, but it will also examine the effects of bias and discrimination on cancer risk,” said Robert W. Haile, DrPH, MPH, associate director of Population Sciences at Cedars-Sinai Cancer and director of the Cancer Research Center for Health Equity, the Cedars-Sinai Chair in Cancer Population Health Sciences and a co-principal investigator of the study. “This is the first large-scale study to look at these effects on cancer risk in Asian Americans.”

Information will be gathered through online questionnaires, Haile said. Participants will not need to visit Cedars-Sinai in person to take part in the study, though staff fluent in multiple languages will be available to assist participants who prefer to complete questionnaires in person or by phone.

As a medical center with access to large Asian American populations and nationally recognized expertise in community outreach and engagement, Cedars-Sinai is charged with enrolling 4,680 participants from various Asian American communities, including Asian Indian, Bangladeshi, Cambodian, Filipino, Korean, Pakistani, Thai and others.

“We will be able to do this quickly because of the infrastructure we have in place,” Surani said. “We are ready to start meeting with trusted community leaders, such as pastors and leaders of community organizations, to disseminate information about the study. They can reach thousands of people at a time.”

The study was motivated by research showing large disparities in cancer rates among various Asian American populations, Haile and Surani said. These include sharp increases in certain cancers: breast cancer in Korean and Filipino women, thyroid cancer across all Asian ethnicities, and lung cancer among Asian American women who have never smoked.

“We don’t know why this is happening, and no one has studied Asian Americans on this scale before,” Haile said. “Most of the studies that exist are small in scale and look at people who have already developed cancer. This is the first study that starts with Asian Americans who don’t have cancer and then follows them over time to see who develops cancer and who does not.”

The plan is to follow these participants for decades into the future, but the first preliminary information about risk factors and demographics could be released at the end of the first year, Haile said.

“Cedars-Sinai Cancer serves one of the most diverse populations anywhere, and a key part of our mission is to bring equity to every aspect of our research and patient care,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “Studies such as this one allow Cedars-Sinai Cancer to contribute invaluable insights into the needs of our cancer community.”

This work is a leading effort and part of a broader Cedars-Sinai strategy to engage diverse patients, according to Michael Farkouh, MD, associate dean for Research and Clinical Trials at Cedars-Sinai. Farkouh said the institution is committed to learning more about the diverse patients it serves and finding ways to understand the unique challenges faced by Asian Americans.

“Finding opportunities to serve patients who have historically been underrepresented is a real challenge in clinical research, and one that people often aren’t aware exists,” Farkouh said. “Community engagement is a cornerstone of Cedars-Sinai’s work and building it out even further can help participants feel safe and supported, leading to even greater local and global impact.”

Read more from Discoveries: Cancer Prevention in Every Language

Radiation therapy is part of the standard treatment for advanced lung cancer, but can cause heart rhythm abnormalities, also called arrhythmias.

In a study published in the peer-reviewed journal JACC: CardioOncology, Cedars-Sinai and Harvard University investigators devised a way to predict, based on the area of the heart exposed to radiation, the type of heart arrhythmia that can result. These findings could help radiation oncologists reduce lung cancer patients’ risk of arrhythmias and identify patients who may need additional cardiac monitoring.

“In this study, radiation oncologists, cardiologists, electrophysiologists and artificial intelligence specialists worked together to intricately map radiation exposure for lung cancer therapy to different regions of the heart,” said Katelyn Atkins, MD, PhD, assistant professor of Radiation Oncology at Cedars-Sinai Cancer, assistant professor of Cardiology at Cedars-Sinai and first author of the study. “We observed that radiation exposure to key structures such as pulmonary veins, coronaries, and atria was associated with distinct arrhythmia types, potentially pointing to unique pathways of injury.”

Additional authors: Samuel C. Zhang, MD; Christopher Kehayias, PhD; Christian Guthier, PhD; John He, BA; Jordan O. Gasho, BS; Mina Bakhtiar, MD; Katrina D. Silos, BA; David E. Kozono, MD, PhD; Paul C. Zei, MD; Anju Nohria, MD; Andriana P. Nikolova, MD, PhD; Raymond H. Mak, MD.

Funding: Dr. Mak has received grant funding from AstraZeneca and ViewRay. Dr. Nohria has received research support from Bristol Myers Squibb; and has received consulting fees from Altathera Pharmaceuticals, AstraZeneca, Bantam Pharmaceuticals, Regeneron Pharmaceuticals, and Takeda Oncology.

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In this study, investigators looked at data from more than 48,000 patients in the National Cancer Database. Based on preoperative imaging, all of the patients in the study had either stage 1 or stage 2 pancreatic cancer.

Following surgery to remove their tumors, more than 78% of stage 1 patients and more than 29% of stage 2 patients were upstaged—generally to a stage that includes lymph node involvement.

“Our research reveals that staging—essential for making treatment decisions and determining research eligibility—is often inaccurate in early-stage pancreatic cancer,” said Srinivas Gaddam, MD, associate director of Pancreatic Biliary Research at Cedars-Sinai and senior author of the study. “As the field is racing toward earlier diagnosis, early staging will become increasingly important.”

Diagnosis and staging of pancreatic cancer are difficult for the same reason. The pancreas, a digestive organ, is located deep in the body and current imaging technology isn’t always able to detect smaller tumors or lymph node involvement, said Gaddam, who is also an associate professor of Medicine and runs the Pancreatic Cancer Screening and Early Detection Program at Cedars-Sinai.

Lymph nodes, clusters of small immune structures, are an important factor in cancer staging and a key difference between early-stage and later-stage pancreatic cancer.

“Patients who have lymph node involvement have a worse survival rate than those without lymph node involvement,” Gaddam said. “When imaging is unable to detect lymph node involvement, staging may not reflect the true extent of the disease. Our findings suggest that lymph node involvement is being missed in four out of every five patients during the staging process.”

The five-year survival rate for stage 1 pancreatic cancer is more than 83%, but that drops to just 3% for patients with stage 4 disease—which is when most patients are currently diagnosed.

“Pancreatic cancer is a difficult diagnosis and there is a tremendous need to improve outcomes for patients,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “Through leading-edge tools, such as our Molecular Twin Precision Oncology Platform, we are developing tests that will guide precision treatment of pancreatic and other cancers. We first demonstrated the utility of Molecular Twin by identifying new biomarkers for pancreatic cancer; these biomarkers assist in the diagnosis, which must be coupled with accurate cancer staging to appropriately guide therapeutics.”

Gaddam’s take-home message for clinicians staging pancreatic cancer is to recognize the limitations of current imaging technology and actively assess and report lymph node involvement. And for those at the forefront of innovation, he stresses the urgent need to improve screening and diagnostic technologies.

Pancreatic cancer screening employs MRI and endoscopic ultrasound. Screening is recommended for people with a family history of pancreatic cancer and those who carry variants in certain genes associated with the disease.

“We know that our current screening and staging tools aren’t great,” Gaddam said. “My hope is that within the next 10 years, we will develop advanced tools for screening and staging pancreatic cancer, allowing us to diagnose most patients at stage 1 and stage 2 rather than stage 4. With these advancements, we can catch this disease much earlier, improving outcomes for many more patients.”

Additional Cedars-Sinai authors of the study: Gerardo Perrotta, MD; Ghada Mohamed, MD; Brent K. Larson, DO; Arsen Osipov, MD; Cristina R. Ferrone, MD; Simon K. Lo, MD.

Funding: Srinivas Gaddam received funding from the AGA (American Gastroenterological Association) Research Foundation’s 2022 AGA-Bern Schwartz Family Fund Research Scholar Award in Pancreatic Cancer for time dedicated to research.

Learn more on the Cedars-Sinai Blog: Pancreatic Cancer Clinic Saves Time and Lives

Pancreatic cancer is one of the most aggressive types of cancer, with an incidence rate that is steadily rising each year. While treatments have improved over the past decade, the five-year overall survival rate for the disease is still just 13%.

The research, led by Cristina Ferrone, MD, the Lippman Family Chair in Surgical Oncology and chair of the Cedars-Sinai Jim and Eleanor Randall Department of Surgery, sought to understand two elements of pancreatic cancers.

First, Ferrone and fellow investigators studied how human leukocyte antigen (HLA) class I complex—a system that presents targets to the immune system, thereby alerting the immune system that a cell is defective—is expressed to a varying degree in pancreatic cancers. If a patient has high levels of HLA class I expressed on the pancreatic cancer, it suggests that their body is better at fighting the cancer.

Next, investigators aimed to target a molecule called B7-H3, which is expressed on malignant cells to escape recognition and destruction by the immune system. In many patients, a high level of B7-H3 means that cancer cells can evade the body’s immune system.

The study, which was completed when Ferrone was a professor of Surgery at Harvard Medical School, found that B7-H3 was highly expressed in the majority of pancreatic cancers studied, and its immune-evading presence was associated with significantly worse patient survival.

Patients whose tumors had a low or negative B7-H3 expression but positive HLA class I expression—alerting the immune system of defective cells—had significantly improved survival.

However, patients with high B7-H3 expressions had consistently poor prognoses, regardless of their tumor’s HLA class I expression.

“Our research suggests that the positive impact provided by high HLA class I expression in pancreatic cancer may be overpowered by a high B7-H3 expression,” said Ferrone, corresponding author of the study. “These findings provide the rationale to leverage B7-H3 suppression as a target for immunotherapeutic approaches, such as CAR-T cells directed to B7-H3, as a strategy for pancreatic cancer patients to potentially improve survival.”

Ferrone said that, in recent years, physicians are trying to shift the therapeutic paradigm for the treatment of pancreatic cancer from a generalized chemotherapy approach to a more patient-specific precision medicine approach based on the individual characteristics of a patient’s tumor. She said that the results of this study indicate a rationale for the design of new Phase I/II clinical trials investigating the effectiveness of anti-B7-H3 monoclonal antibodies alone or in combination with standard of care chemotherapy regimens, as well as a CAR-T therapy aimed at B7-H3 for patients with pancreatic cancer.

“If trial results from this approach are positive,” Ferrone said, “targeting B7-H3 has the potential to significantly improve the efficacy of immunotherapies for pancreatic cancer patients and, eventually, overall survival rates for the disease.”

Additional authors include Giulia Cattaneo; Marco Ventin; Shahrzad Arya; Filippos Kontos; Theodoros Michelakos; Yurie Sekigami; Lei Cai; Vincenzo Villani; Francesco Sabbatino; Francine Chen; Ananthan Sadagopan; Vikram Deshpande; Paul A. Moore; David T. Ting; Nabeel Bardeesy; Xinhui Wang; Soldano Ferrone.

Funding: This work was supported by National Cancer Institute/National Institute of Health (NCI/NIH) grants [R03CA223886 and R03CA231766 to Cristina Ferrone and Soldano Ferrone; R01DE028172 and R01CA226981 to Xinhui Wang], Department of Defense Breakthrough Award Level 2 [W81XWH-16-1-0500 (BC190615) to Soldano Ferrone], Department of Defense Breakthrough Award Level 4 [W81XWH-20-1-0315 (BC190615) to Cristina Ferrone and Soldano Ferrone], Department of Defense Idea Award [W81XWH-20-PCRP-IDA (W81XWH2110433) to Xinhui Wang] grants, and Internal funding from the Department of Surgery at the Massachusetts General Hospital.

Read more from the Cedars-Sinai Blog: How to Manage Your Pancreatic Cancer Risk

The findings were recently published in the American Journal of Human Genetics.

In total, investigators used data from more than 26,000 women with ovarian cancer and 100,000 women without the disease. Investigators then confirmed 27 risk regions—meaning areas within an individual’s genetic makeup—that could make women more susceptible to developing ovarian cancer.

“The big takeaway is that multiple genetic variants are associated with the risk of ovarian cancer, but the risks of each variant are small,” said Paul Pharoah, MD, PhD, professor and research scientist in the Department of Computational Biomedicine at Cedar-Sinai, and corresponding author of the study.

How to decipher this risk, however, comes down to genetics.

“We used a variety of bioinformatic approaches to identify multiple genes that are likely to be important in the biology of ovarian cancer risk,” Pharoah said.

The findings provide a framework for improving disease prediction and prevention, according to Pharoah and Michelle Jones, PhD, a study author and assistant professor and co-director of the Applied Genomics, Computation and Translation Core in the Department of Biomedical Sciences.

“In this study we have continued to learn more about how differences in our DNA sequence change the way our genes are expressed in a way that may lead to the development of cancer,” Jones said. “It took a large team of diverse scientists working together to make this project a success, with each bringing unique expertise to the challenge.” 

As a next step, the Ovarian Cancer Association Consortium is analyzing how best to combine the risk information from multiple-risk genetic variants.  

“We are particularly interested in optimizing polygenic risk models in women from diverse ancestries, which have the potential utility to identify women at high risk of ovarian cancer who may benefit from preventive interventions,” Pharoah said.

Other Cedars-Sinai investigators involved in the study include Simon G. Coetzee, Dennis Hazelett, Pei-Chen Peng and Marc T. Goodman.

The analyses presented in this manuscript have been funded in part by NIH/NCI grants: R01CA207456, R01CA204954, R01CA211707, R01CA211575, R01CA207456, R21CA220078, R00CA256519 and U19C8804/A7058. A proportion of funding was provided as part of an Institutional commitment to The Center for Bioinformatics and Functional Genomics at Cedars-Sinai Medical Center.

Read more from the Cedars-Sinai Newsroom: Cancer Epidemiologist Sees Collaboration As Key to Research Success

is the first step toward a better understanding of EV biology and the development of new clinical tests to measure disease progression in real time.

“Our hope is to be able to associate different EV fingerprints with different diseases and responses to treatment,” said Dolores Di Vizio, MD, PhD, professor of Urology, co-leader of the Cancer Biology Program at Cedars-Sinai Cancer and co-senior author of the study. “As cancer scientists, we are primarily interested in applying this new technology to the creation of ‘liquid biopsy’ tests for cancer detection. However, because all cells in the body produce EVs, we also envision its future use to identify biomarkers of cardiovascular disease, autoimmune diseases or neurological disorders.”

EVs are made of an outer envelope of fat molecules filled with “cargo” that might include RNA, proteins and lipids. The tiny particles vary greatly in size, with the largest being about one-tenth the width of a human hair.

“Prior to this study, EVs were mainly classified by their size and by how they were generated,” said Andries Zijlstra, PhD, adjunct associate professor of Pathology, Microbiology and Immunology at Vanderbilt University Medical Center and co-senior author of the study. “The goal of this study was to create a technology that could classify EVs based on several of their characteristics and their various combinations.”

EVs are studied using flow cytometry. The particles are separated from a blood sample, then suspended in fluid flowing through a laser beam that measures their physical and chemical characteristics.

To create the new technique of EV fingerprinting, investigators measured 20 different EV characteristics and used machine learning to classify various combinations of membrane composition, cargo, size and method of generation.

“The concept is that cells in different disease states will produce EVs with a unique fingerprint,” Di Vizio said. “For instance, we have prostate cancer cell lines, and each of these lines now has an EV fingerprint associated with it.”

A further advantage of EV fingerprinting is that it can be performed directly from a blood sample without the laborious process of separating out the EVs, Di Vizio said. This means the technology can be used to develop “liquid biopsy” tests that can be used in clinics.

“Our EV fingerprinting method is faster than most liquid biopsy approaches that require the isolation of EVs,” Di Vizio said. “These tests could be used for diagnosis, monitoring progression of disease and response to treatment, and perhaps even predicting patient outcomes.”

Investigators will next explore pairing specific EV fingerprints with specific disease states, beginning with aggressive forms of cancer, Di Vizio said.

“This type of translational science is key to our mission at Cedars-Sinai Cancer,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair and Director at the Samuel Oschin Comprehensive Cancer Institute. “By developing practical new testing techniques that allow us to precisely measure the state of a patient’s health, we can promote the concept of ‘precision prevention,’ expand the promise of precision therapy in oncology and save patients’ lives.”

Funding: This work was supported in part by grants from the National Institutes of Health (R01CA218526 to AZ and DDV; R01CA234557 to 1183 DDV; R01CA249424 to HP and AW; P01CA229123, R01CA206458, R01CA249684 and U01CA224276 to AMW) and the National Science Foundation (NSF-2328276 and NSF-2036809 to AMW and JTW).

Additional authors include Tatyana Vagner, Ariana K. von Lersner, Fabiane Fernandes, Patricia Midori Murobushi Ozawa, Marques Jackson, Matthieu Masureel, Hoangdung Ho, Sierra M. Lima, Tatyana Vagner, Bong Hwan Sung, Mohamed Wehbe, Kai Franze, Heather Pua, John T. Wilson, Jonathan M. Irish and Alissa M. Weaver.

Read more on the Cedars-Sinai Blog: Study Sheds Light on How Cancer Spreads in Blood

team.

“I’m excited about helping Cedars-Sinai Cancer team members in the Department of Radiation Oncology to develop their passions and their careers, and I’m passionate about translating their research ideas into patient benefit,” Chetty said. “Cedars-Sinai Cancer is built to support these endeavors.” 

Chetty comes to Cedars-Sinai from Henry Ford Health in Detroit, where he was professor and director for the Medical Physics Division and vice chair of Academics for the Department of Radiation Oncology at Henry Ford Cancer Institute.

“Dr. Chetty brings to Cedars-Sinai Cancer a wide range of experience that is perfectly aligned with his new role,” said Howard Sandler, MD, chair of the Department of Radiation Oncology and the Ronald H. Bloom Family Chair in Cancer Therapeutics at Cedars-Sinai. “His expertise in overseeing and coordinating clinical operations, further developing our research infrastructure, and teaching and leading strong teams of physics and medical residents will serve our department well.”

Chetty earned his PhD in medical physics from UCLA, then served as assistant professor of Radiation Oncology Physics at the University of Michigan. He was mentored there by Benedick Fraass, PhD, a distinguished medical physicist and radiation oncology pioneer. In 2011, Fraass left the University of Michigan to join Cedars-Sinai, where today he is professor emeritus in the Department of Radiation Oncology. Chetty has stepped in to fill his mentor’s previous position.

“Joining Cedars-Sinai Cancer represents a full-circle moment for me, in that I get to come back to Los Angeles and join up again with Dr. Fraass, my mentor and inspiration,” Chetty said. “Dr. Fraass is one of the most accomplished medical physicists in the field, so I have huge shoes to fill, but it’s an honor to be able to build on all that he accomplished at Cedars-Sinai.”

Fraass said he is thrilled that Chetty is taking on the role he filled for 12 years.

“I am sure Dr. Chetty will continue to enhance the dramatic growth in clinical care quality, education, and research and development that the division and the Department of Radiation Oncology have accomplished in the past 10 years,” Fraass said.

Chetty, a fellow of the American Society for Radiation Oncology and the American Association of Physicists in Medicine, has received numerous research grants, including five R01 grants from the National Cancer Institute. His most recent research centers on the development of imaging techniques that can predict treatment outcomes and personalized therapy for cancer patients. He also is versed in the use of machine learning to automate processes that improve patient outcomes and safety.

Read more on the Cedars-Sinai Blog: Radiation | Your Questions Answered

“We identified a new subtype of cells surrounding therapy-resistant soft tissue sarcomas,” said Jlenia Guarnerio, PhD, a research scientist at Cedars-Sinai Cancer and senior author of the study. “These cells secrete a molecular ‘Velcro’ called CXCL16 that traps immune cells, especially T cells, and keeps them from entering the tumor. With very few T cells inside the tumor, available immunotherapies aren’t effective.”

Soft tissue sarcomas originate in muscle, fat, blood vessels, nerves, tendons and joint lining, and can occur anywhere in the body. Some of these tumors do not respond to immunotherapy, which helps the body’s own immune system fight cancer cells, said Marina Broz, a PhD student in the Guarnerio Lab at Cedars-Sinai and first author of the study.

“Previous studies have shown that cells called cancer-associated fibroblasts prevent immune cells from entering these tumors, leading to therapy resistance, but the way they achieve this is poorly understood in many cancers and particularly in soft tissue sarcomas,” Broz said.

Investigators found a particular subtype of cancer-associated fibroblasts surrounding therapy-resistant soft tissue sarcomas in laboratory mice.

“These are the cells that are trapping T cells outside the tumors,” Broz said. “And we noted that they rely on glucose to make energy, which turned out to be the key to turning non-responding tumors into responders.”

When investigators treated the mice with a glycolysis inhibitor to stop the cells from using glucose, the fibroblasts no longer secreted CXCL16—and T cells invaded the previously therapy-resistant tumors. This dramatically improved the abundance of T cells, thus making the tumors more vulnerable to chemotherapy as well.

“Without the inhibitor, the tumors were barely responsive to therapy,” Guarnerio said. “The inhibitor alone didn’t reduce tumor growth at all, but in combination with chemotherapy it significantly reduced tumor growth.”

Because glycolysis inhibitors aren’t safe for patients, investigators will work to develop a therapy to target CXCL16, said Guarnerio, who is also an assistant professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai.

“Targeting CXCL16 could also improve outcomes for patients with other types of immunotherapy-resistant tumors,” Guarnerio said. “We would like to see if we can engineer a therapy to improve treatment response in all tumor types with poor T cell infiltration.”

Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair, said that the study is an example of translational research that may produce targeted therapies.

“This work represents our commitment at Cedars-Sinai Cancer to the promise of precision medicine, which may produce targeted therapies and further enhances our clinical adult and pediatric sarcoma program,” Theodorescu said.

Additional Cedars-Sinai authors participating in this study included Emily Y. Ko, Kristin Ishaya, Jinfen Xiao, Marco De Simone, Xen Ping Hoi, Roberta Piras, Basia Gala, Fernando H. G. Tessaro, and Anja Karlstaedt.

Other authors included Sandra Orsulic, Amanda W. Lund, and Keith Syson Chan.

Funding: J.G. was supported by the K99/R00 grant (CA212200) and R01 (CA258265) for the execution of this work. Additionally, J.G. was supported by grants from the Sarcoma Foundation of America (Grant 2019 SFA 15–19), and the Cedars-Sinai Cancer Accelerator Award. M.B. was supported by a National Cancer Institute F31 fellowship (1F31CA284888). K.S.C was supported by R01CA175397, R01CA175397-Supplement, U54CA274375. X.P.H received funding from U54CA274375. A.W.L. received support from the Cancer Research Institute (Lloyd J. Old STAR Award). A.K. was supported by the National Heart, Lung and Blood Institute (R00 HL141702) and the Leukemia Research Foundation New Investigator Award (Grant No. 941997).

Read more on the Cedars-Sinai Blog: Immunotherapy – The Fourth Pillar of Cancer Care

Zheng will work with Cedars-Sinai surgical and medical oncology leadership to develop and lead a comprehensive translational and basic science research program for melanoma.

“Dr. Zheng’s expertise in melanoma research and focus on translating his findings into personalized and targeted immunotherapies will strengthen our knowledge around prevention, diagnosis and treatment of melanoma, the deadliest form of skin cancer,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “We are thrilled to have Dr. Zheng on our team and look forward to continued progress for patients with melanoma.”

Zheng’s research focuses on the metabolism of melanoma cancer cells and the tumor microenvironment—the cells and tissues surrounding a tumor. The tumor microenvironment has been implicated in resistance mechanisms to current immunotherapies, including checkpoint inhibitors, which use a patient’s own immune system to fight cancer. He also is working to enrich current understanding of resistance to today’s targeted therapies.

“Melanoma is a difficult cancer to treat, and collaborating with my peers to improve survival through better treatments is my goal,” Zheng said. “We’ve made a lot of progress in targeted immunotherapies over the last decade. There are still many challenges, but we’ve made important scientific discoveries that could translate into new therapies for melanoma patients.”

Zheng earned his PhD in molecular pathology from the University of California, San Diego (UCSD), and completed his postdoctoral fellowship at Harvard Medical School, Beth Israel Deaconess Medical Center. He served as assistant professor of Dermatology, Pathology and Cell Biology at the Institute for Cancer Genetics at Columbia University and as associate professor of Dermatology at Harvard Medical School before joining Cedars-Sinai Cancer.

“We have made significant contributions to patient survival through our Cutaneous Malignancies Disease Research Group and Early Phase Developmental Therapy Program,” said Omid Hamid, MD, co-director of the Cutaneous Malignancies Disease Research Group at Cedars-Sinai Cancer and chief of Translational Research and Immuno-Oncology at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate. “We are eager to collaborate with Dr. Zheng to use critical data from his basic research through trials to improve patient outcomes, and to test innovative new therapies that could save lives.” 

Mark Faries, MD, surgical director of the Melanoma Program in Cedars-Sinai Cancer, said survival rates for melanoma continue to improve because of investigators like Zheng.

“Our team looks forward to translating Dr. Zheng’s promising discoveries into more advanced and effective treatment options for patients with melanoma,” said Faries, co-director of the Melanoma Program and head of Surgical Oncology at The Angeles Clinic and Research Institute. “It’s an exciting time in melanoma research, and Dr. Zheng’s presence positions us well to capitalize on leading-edge advances and pursue exciting new discoveries.”

Read more on the Cedars-Sinai Blog: What You Need to Know About Melanoma

, and colleagues organized a meeting in Cambridge, UK, to bring together researchers from around the world studying the genetics of ovarian cancer. It led to the creation of the Ovarian Cancer Association Consortium (OCAC). Nearly 20 years later, the collaborating scientists are still working together.

“Almost everything we know about the genetics of ovarian cancer has come from this consortium, and that's involved working together,” he said.

Now, as professor and research scientist in the Department of Computational Biomedicine since 2022, Pharoah aims to work with colleagues across departments and laboratories at Cedars-Sinai to make similar inroads in tough-to-treat diseases.

Pharoah was previously professor of Cancer Epidemiology at the University of Cambridge where he led a research group studying how the genetic variants that people inherit alter risk for hormone-related cancers, and how patient and tumor characteristics affect chances of survival after a diagnosis of cancer. His research into prognostic factors led him to create two online tools that help clinicians make treatment decisions: PREDICT Breast Cancer and PREDICT Prostate. His work was recognized with the John Graunt Prize for Extraordinary Achievement in Population Sciences in 2016.

Pharoah spoke with the Cedars-Sinai Newsroom about new collaborations he looks forward to forming.

What has made your collaborations possible?

OCAC has been successful because we all shared the same vision for the sort of science we wanted to do, and we were willing to share data to make it happen. My team has collaborated with investigators from Cedars-Sinai for years, which is part of the reason I came here. Simon Gayther, PhD, was one of the founding members of OCAC, and Michelle Jones, PhD, joined seven years ago. In the past seven years, we have worked very closely on several consortium projects and the OCAC database is now hosted by us at Cedars-Sinai.

What inspired you to create the PREDICT websites?

I wanted to apply data on how different cancers behave and how people respond to treatment to develop tools to help oncologists personalize their approaches and guide their discussions with patients. The tools can explain the probabilities of a patient surviving depending on the treatment they get, and how different combinations of treatments might affect those percentages.

What projects are you currently working on?

My colleagues in Computational Biomedicine and I will develop the PREDICT tools further so they can incorporate data from a more diverse population than the initial data from the UK model.  

We're particularly interested in seeing how well the PREDICT Breast Cancer tool performs with women of African ancestry and women of Latin ancestries. One of our plans is to incorporate U.S. national data and data from Cedars-Sinai.

Looking ahead, what excites you most about the clinical applications of cancer epidemiology?

On the ovarian cancer genetics front, I would hope that in the next few years, with all the whole genome sequencing data that's becoming available from various biobanks around the world, we'll be able to use those data to continue to unravel the inherited basis of ovarian cancer.

We would like the opportunity to expand the PREDICT model into other cancers. There is a team in the UK working on kidney cancer prediction, and there's potential for doing work on colorectal cancer.

I'm also enjoying work on molecular pathology. We would like to start using some of the newer techniques such as spatial transcriptomics and spatial proteomics to investigate more complex patterns in the molecular pathology of ovarian cancer, and how they relate to clinical outcomes. We are particularly interested in studying the role of tumor immune cells.

When it comes to ovarian cancer, what we understand about the biology says patients should respond to immunotherapy, but, in fact, they often don't. There is work to be done in understanding what it is about the immune environment in this cancer that prevents response to immunotherapy. This is an area of research that is developing rapidly.

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Active surveillance is an established practice for managing certain low-risk cancers that are unlikely to cause harm. It is an increasingly common and effective way to manage certain early-stage cancers, including those in the prostate, thyroid and kidney. However, adoption of active surveillance in practice has been hit-and-miss for several reasons. Among them, according to multiple studies, is a perceived increased risk of malpractice among physicians, stemming from unease that the window for a cure may unexpectedly close.

In a new study, Cedars-Sinai Cancer investigators explored malpractice trends related to active surveillance as a treatment strategy across cancers. They found that to date, there has been no successful litigation related to active surveillance. Their research was recently published in the peer-reviewed journal Annals of Surgery.

BACKGROUND  

Cancer clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) consider active surveillance an effective strategy for managing low-risk prostate, kidney and thyroid cancers. Active surveillance is also considered standard of care for certain lymphomas and an emerging option for managing stage 0 breast cancer. This less-invasive approach reserves surgery for cases in which the cancer progresses. In doing so, it avoids the adverse side effects of treatment when the benefit of that treatment (surgery, chemotherapy) is unclear.

Because some cases do progress, physicians have indicated a reluctance to use active surveillance for fear of malpractice lawsuits. However, data on malpractice trends across cancers had previously been lacking.

METHODS

Cedars-Sinai Cancer investigators analyzed comprehensive data from Westlaw Edge and LexisNexis Advance databases between 1990 and 2022 and examined federal and civil medical malpractice cases in all 50 states involving active surveillance for lymphoma and thyroid, prostate, kidney and breast cancer.

They found five prostate cancer cases related to active surveillance; no pertinent cases were found regarding active surveillance in any other cancers. In two of the five prostate cancer cases, the court defended the practice of active surveillance, determining that it was in accordance with national standards of “sound clinical judgment” and “accepted medical practices.” The other cases involved alleged physician negligence for not having recommended active surveillance as a treatment option, after the patients had complications from surgery. All cases were ruled in favor for the physicians, who had documented informed consent for active surveillance.

IMPACT

The authors concluded that given the legal precedent detailed in the identified cases—and increasing support across national guidelines—active surveillance is a sound management option in appropriate low-risk cancers and appears to present no increased risk of malpractice litigation.

“Our team previously published research showing that active surveillance is an effective treatment for many low-risk thyroid cancer patients,” said Allen Ho, MD, lead author of the study and co-director of the Thyroid Cancer Program at Cedars-Sinai Cancer. “These latest findings show no increased risk of medical malpractice with active surveillance across multiple cancer types.”  

“This data should bolster physicians’ confidence in recommending active surveillance for their patients when it is an appropriate option,” said Timothy Daskivich, MD, co-author of the study and assistant professor of Surgery at Cedars-Sinai. “Active surveillance maximizes quality of life and avoids unnecessary overtreatment, and it does not increase medicolegal liability to physicians, as detailed in the case dismissals identified in this study. In fact, in some cases, physicians were sued because they didn’t offer active surveillance.”

The authors added that failure to discuss an NCCN-recommended approach as a treatment option with patients could be considered just as prone to litigation. Their recommendations to strengthen patient communication and guard against malpractice include thoroughly explaining active surveillance to patients, engaging with the institution’s compliance officers or legal counsel to develop standardized consent templates, and integrating patient preferences and personal values when proposing the treatment option. 

AUTHORS 

Other Cedars-Sinai authors include Missael Vasquez, Wendy Sacks, MD, and Zachary Zumsteg, MD.

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could help physician-scientists who obtain patient consent to extract information from these patients’ pathology reports for research and clinical trial recruitment.

“Cancer is a complex disease, and rich information is contained in the notes that a pathologist makes when they review a patient’s cancer underneath the microscope,” said Nicholas Tatonetti, PhD, vice chair of Operations in the Department of Computational Biomedicine at Cedars-Sinai, associate director of Computational Oncology at Cedars-Sinai Cancer and senior author of the study. “But because these notes are in the form of scanned PDFs, the text they contain has been inaccessible to computers—until now.”

To create a machine-readable pathology dataset, Tatonetti and his team worked with The Cancer Genome Atlas, a publicly available collection of information from thousands of U.S. cancer patients who have given permission for investigators to examine their personal health records.

“The pathology reports in the atlas are scanned in at all angles and in different formats from each of the institutions that provided them,” Tatonetti said. “They’re messy and their scan quality is relatively poor—not unlike pathology forms you would find in patient records.”

Investigators used AI to clean up the scans so that optical character recognition software could turn them into machine-readable notes. When investigators compared these notes against the original reports, they found this method was highly accurate.

“By making the reports machine readable, we can train algorithms to extract information from them in response to investigators’ questions,” Tatonetti said. “This will help investigators identify and validate new disease markers, conduct research, and recruit patients for clinical trials.”

The resulting collection of text from the reports, now publicly available, includes data on almost 10,000 cancer patients. The format is commonly used in machine learning to allow computational biologists and computer scientists to use the data, Tatonetti said. The method could also be used to extract pathology report data from other datasets.

“The true story of a patient’s condition, such as detailed information about their cancer and the effects of various therapies, is found in clinicians’ notes,” said Cedars-Sinai Cancer Director Dan Theodorescu, MD, PhD, the PHASE ONE Foundation Distinguished Chair and Director at the Samuel Oschin Comprehensive Cancer Institute. “Tools that help us mine this information further our efforts to conduct translational studies that bring the promise of precision medicine to each of our patients.”

Tatonetti and his team are now focused on training models to extract specific information—such as cancer staging—from the data.

“Our model can extract that information when it is present in the notes, but it can also accurately infer the stage when it is not explicitly stated,” Tatonetti said. “For instance, the pathologist might make a note about a secondary lesion or about or evaluating a sample of a breast cancer from the liver. These notes don’t include the word metastatic, but they do imply it.”

The team is also working to apply its method to the Molecular Twin Precision Oncology Platform, a unique precision medicine and AI tool created at Cedars-Sinai that includes pathology reports and other data on the majority of Cedars-Sinai’s cancer patients. Team members are also developing tools to make other clinician notes from patient records machine readable, Tatonetti said.

“AI enhancements to optical character recognition are the key to extracting a wealth of data from some of the most clinically relevant portions of patient records,” said Jason Moore, PhD, chair of the Department of Computational Biomedicine at Cedars-Sinai. “This data will fuel new studies by researchers across specialties, including research clinicians, clinical trial investigators and investigators working to improve tools that allow computers to interpret clinical language.”

Funding: This work was supported by National Institute of General Medical Sciences of the National Institutes of Health grant number R35GM131905.

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found that for some patients with this difficult-to-treat cancer, radiation therapy plus immunotherapy could yield the best tumor-fighting immune response prior to surgery.

“Our most important finding was identifying these three different patient groups,” said Simon Knott, PhD, co-director of the Applied Genomics Shared Resource at Cedars-Sinai Cancer and senior author of the study.

One group, Knott said, didn’t respond at all to therapy, one responded well to immunotherapy, and one responded only to immunotherapy plus radiation therapy. “This could help us employ our most aggressive treatment options only when needed most,” Knott said. 

Triple-negative breast cancer is so called because its cells test negative for receptors to the hormones estrogen and progesterone, and for a protein called HER2. These tumors, which account for 10%-15% of breast cancers, grow and spread faster than other types, and in general have fewer treatment options.

Patients with triple-negative breast cancer generally receive treatment to shrink their tumors before having surgery. Immunotherapy, which uses a person’s own immune system to fight cancer, is part of that pre-surgical treatment.

“Triple-negative breast cancer is the only type of breast cancer we treat with immunotherapy,” said Stephen Shiao, MD, PhD, co-director of the Cancer Therapeutics Program at Cedars-Sinai Cancer and first author of the study. “Unfortunately, only 20% to 30% of patients respond to immunotherapy on its own. Combining it with chemotherapy boosts response to 60% but exposes patients to significant toxicity.”

To determine whether a combination of radiation therapy and immunotherapy would improve patient response, investigators launched a clinical trial. During the trial, they examined tumors from 34 triple-negative breast cancer patients.

Patients underwent biopsies before treatment, after one course of immunotherapy, and after a second course of immunotherapy plus radiation therapy. Investigators then analyzed the biopsied tissues.  

They used single-cell genetic profiling to identify the cancer cells and different types of immune cells making up each tumor. They also looked at proteins expressed by cells, mapping their positions and permitting a better understanding of how the different cells interact.

The analysis yielded profiles for three types of responders, Knott said.

“We saw that tumors of patients who didn’t respond at all to pre-surgical therapy had no immune cells in them, and tumors of patients who responded right away to immunotherapy were packed with certain types of immune cells,” Knott said. “That wasn’t surprising. But we found another group of patients with tumors that looked quite similar to the tumors of non-responders, and didn’t respond to the initial round of immunotherapy. However, they did respond after the combination of immunotherapy and radiotherapy. After the combination therapy, immune cells invaded the tumors, and the tumors shrank.”

Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair, said that the study’s findings suggest radiotherapy may positively impact immune response in these tumors.

“This study will guide investigators toward the next generation of clinical trials,” Theodorescu said. “The investigators also describe a new framework for mapping the distribution of immune cells within tumors, and that could help us identify new precision medicine approaches for patients with breast and other cancers.”

Investigators’ next task is to find practical ways to identify these responder groups in a clinical setting, via blood samples or other means, to better tailor treatments. They will also explore the possibility of combining radiotherapy with other types of immunotherapy prior to surgery, as a way to improve response for high-risk patients, Shiao said.

Funding: The study was supported by Department of Defense Breast Cancer Research Program grants W81XWH-19-1-0600, W81XWH-19-1-0070, and W81XWH-19-1-0599; the Breast Cancer Research Foundation; and National Cancer Institute grants CA220000 and CA191139. 

Read more on the Cedars-Sinai Blog: Style and Grace – Salon Owner Overcomes Breast Cancer

“Ours is the first study to show that the liver has protective mechanisms for defending itself against cancer,” said Shelly Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai and senior author of the study. “We discovered that two proteins in healthy liver cells, working together, curb the action of a third protein that makes the liver a fertile place for cancer to grow.”

Cancer that originates in the liver is one of the leading causes of cancer death. The liver is also a common site for cancer to spread to—most often from colorectal cancer.

“Harnessing the power of the body’s own defense mechanisms represents a promising way forward in the battle against some deadly cancers,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “This study builds on years of work and is an important step in that direction.”

Two proteins long studied by Lu—prohibitin 1 and methionine adenosyltransferase 1A—are found in healthy liver cells. Previous research by Lu and her team has shown that when either of these proteins is missing in laboratory mice, the mice develop liver cancer, but investigators didn’t yet understand fully why this happens.

“We have been studying these two proteins for several decades,” Lu said. “In this new study, we found that they work together to suppress a particular protein called matrix metalloproteinase-7, which is well known among cancer researchers as one that breaks down the matrix that holds cells together and allows invasion of cancer cells to occur.”

In their latest study, investigators found that prohibitin 1 and methionine adenosyltransferase 1A partner together to shut down expression of cancer-promoting matrix metalloproteinase-7.

“This prevents cancer from taking hold,” Lu said.

Investigators edited the DNA of laboratory mice to knock out expression of the partnering proteins. In some of those mice, investigators also knocked out expression of the cancer-promoting protein. They then studied what happened in a mouse model of colon cancer liver metastasis.

“We found that with either of the partnering protective proteins eliminated, the mice were wildly sensitive to cancer metastasis,” Lu said. “It grows like wildfire. But if you also silence the cancer-promoting protein, that sensitization is gone and the cancer does not grow. This provides strong evidence that it is the cancer-promoting protein that is sensitizing the liver to cancer metastasis, and the combination of the two partnering proteins is keeping its expression down. This is the defense mechanism that no one had yet discovered.”

Investigators will next examine strategies to prevent the partnering protective proteins from being downregulated, so that they suppress the cancer-promoting protein and prevent metastases to the liver, Lu said.

Funding: This study was supported by National Institutes of Health grants P01CA233452 and R01DK123763, Cedars-Sinai Cancer Developmental Funds, Plan Nacional of I+D grant SAF2017-88041-R, and American Heart Association grant 23CDA1052548.

Read more on the Cedars-Sinai Blog: The Liver/Cancer Connection

In this study, the investigators explored combining standard immune checkpoint inhibitors with a new class of immunotherapies called ImmTACs (immune-mobilizing monoclonal T-cell receptors against cancer).

While immune checkpoint inhibitors prevent tumors from deactivating cancer-killing immune cells called T-cells, ImmTACs draw T-cells directly to tumor cells via receptors for T-cells on one side and tumor cells on the other.

“The results of this study point toward new combination treatments that can help patients whose melanoma has progressed despite first-line therapy,” said Omid Hamid, MD, chief of Translational Research and Immuno-Oncology at Cedars-Sinai Cancer at The Angeles Clinic and Research Institute, medical director of the Cutaneous Malignancies Disease Research Group at Cedars-Sinai Cancer, and lead author of the study. “Once these treatments receive regulatory approval, they represent the next set of options for these skin cancer patients.”

The study enrolled 85 patients whose malignant melanomas had progressed despite previous treatment with standard immune checkpoint inhibitor therapy. All were treated with a combination of an ImmTAC and immune checkpoint inhibitors. The combination produced one-year overall survival rates above 76%, with no unexpected side effects.

The ImmTAC used in the study, tebentafusp, is the first drug to be approved by the U.S Food and Drug Administration (FDA) for treating ocular melanoma, the most common type of eye cancer.

While cutaneous melanoma—cancer that forms in the skin’s pigment-producing cells—isn’t the most common form of skin cancer, it is the most lethal, Hamid said. It causes about 10,000 deaths in the U.S. each year by spreading deeper into the skin or to other parts of the body.

Immune checkpoint inhibitors have dramatically improved survival rates for patients whose skin cancer has spread. Many of these drugs—including pembrolizumab, nivolumab, avelumab, ipilimumab, durvalumab and atezolizumab—have been studied by Hamid and his team in first-in-human clinical trials to treat melanoma. Later, the therapies also were approved by the FDA to treat basal and squamous skin cancers, as well as lung, gastroesophageal, endometrial and breast cancers.

“A decade or so ago, median survival for metastatic melanoma was six months,” Hamid said. “But thanks to our ability to harness the power of the immune system, the median survival is now six years and greater. Unfortunately, these immune checkpoint inhibitors don’t work for everyone.”

Previous studies have shown that immune checkpoint inhibitors like nivolumab and pembrolizumab benefit only 30%-40% of patients.

“Adding an ImmTAC to these immune checkpoint inhibitors produced an amazing one-year survival rate,” Hamid said. “This was also the first trial to show that we can safely combine ImmTACs and immune checkpoint inhibitors in patients whose cancer progressed despite treatment with standard immune checkpoint inhibitor therapy.”

This data has now been translated to other clinical trials with ImmTACs that offer options for patients with a wide variety of tumors, including melanomas, sarcomas, and endometrial, ovarian, and non-small cell lung cancers, Hamid said.

Investigators are moving forward with a Phase III trial of the tebentafusp and immune checkpoint inhibitor combination for patients with newly diagnosed cutaneous melanoma.

“The incidence of cutaneous melanoma is increasing dramatically,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “Metastatic disease is difficult to treat, but through innovations and trials, we have made major strides in extending survival for these patients. We are continually exploring cutting-edge therapies to provide new opportunities for these patients.”

Funding: The study was funded by pharmaceutical developer Immunocore Ltd.

Read More on the Cedars-Sinai Blog: Don’t delay getting a skin exam. Here’s what to expect

investigators are spearheading a project, funded by a five-year, $11.2 million grant from the National Cancer Institute, part of the National Institutes of Health, to advance scientific knowledge of how biological differences between men and women affect bladder cancer. They hope to use this knowledge to shape therapies and improve patient outcomes.

“As part of this work, we also hope to define the fundamental principles that influence cancer risk, and to promote cancer research so that investigators begin to take male and female differences into consideration,” said Xue Li, PhD, principal investigator of the project and co-leader of the Cancer Biology Program at Cedars-Sinai. “We can no longer treat males and females as asexual and ignore these differences.”  

Bladder cancer is three to five times more common in men than in women, even after adjusting for environmental factors such as smoking.

“We chose to focus on bladder cancer because the difference in rates between men and women is so dramatic,” Li said.

The difference in incidence isn’t limited to bladder cancer, however.

“Liver, skin, colon, lung, brain and pancreatic cancers are also more prevalent in men than in women, so this is only the beginning of our efforts to understand these important nuances,” Li said.  

The award is a Program Project Grant, a type that is awarded to multidisciplinary teams with shared objectives. Li said it is only the second Program Project Grant for the study of sex as a biological variable that the NCI has awarded in its history.

“We have made efforts to build a world-class research and clinical program in bladder cancer,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “Dr. Li has made a significant contribution since joining Cedars-Sinai, and we are eager to see his research efforts continue to unfold.”

Three research teams—two at Cedars-Sinai and one at The Ohio State University Comprehensive Cancer Center—will each examine sex as a biological variable in bladder cancer from a unique standpoint.

Epigenetics: The X. Li Lab at Cedars-Sinai will examine epigenetic factors that might contribute to the greater prevalence of bladder cancer in men versus women. Epigenetic factors are not part of genes, but can change the way that genes work. Epigenetic factors might influence cells’ vulnerability to being transformed into cancer cells, or might influence the immune system, creating an environment that allows cancerous tumors to grow.

Genetics: The Theodorescu Lab at Cedars-Sinai will focus on the role of the Y chromosome, the male-determining sex chromosome, in bladder cancer. Loss of the Y chromosome (LOY) happens as men age and when they are exposed to carcinogens such as cigarette smoking. LOY in cancer cells allows them to evade the immune system, but also makes them vulnerable to a common treatment called immune checkpoint therapy.

Immunology: The Zihai Li Lab  at the James Comprehensive Cancer Center at The Ohio State University will investigate how signaling of the sex hormone androgen may exhaust immune cells called T-cells. This exhaustion could result in more aggressive cancer, and the work could lead to improvements to immune checkpoint therapy, which helps reverse that exhaustion.

“At our cancer center, we emphasize awareness of sex and gender across the entire spectrum of cancer research and care, not just bladder cancer,” said Theodorescu. “We need to really consider this interplay between the biological sex, the epigenome and the immune system in cancers in order to make the most impactful discoveries for our patients.”

Li said that the Program Project Grant has catalyzed collaboration and synergy among the three teams, “which we hope will be a game changer in the world of bladder cancer—and beyond.”

Read More From Discoveries: Bladder Cancer Breakthroughs

“When patients with Lynch syndrome—whose first cancers generally appear at an early age—aren’t diagnosed promptly, they don’t get appropriate follow-up or surveillance,” said Megan Hitchins, PhD, director of Translational Genomics in the Department of Biomedical Sciences at Cedars-Sinai and lead author of the study. “They can go on to have multiple different cancers before they are finally diagnosed. If we could identify them when they have their first cancer, we could prevent additional cancers—or at least detect them earlier.”

Many colorectal and endometrial cancers have something called mismatch repair deficiency. This means that the tumor formed because of mistakes that occurred when DNA was copied during cell division.

In most cases of Lynch syndrome, this mismatch repair deficiency is caused by an inherited mutation in a DNA mismatch repair gene. But mismatch repair deficiency can also be caused by something called methylation. This is a change to a gene called MLH1.

“Methylation isn’t hard-wired into the gene the way a mutation is,” said Hitchins. “It’s added on, like debris clogging an engine. The engine itself is not defective, but it doesn’t work properly because it’s been clogged.”

MLH1 methylation is present in as many as 75% of tumors with mismatch repair deficiency, Hitchins said. It is usually present only in the tumor, meaning the defect is not inherited and the patient does not have Lynch syndrome.

“However, our study found that in a small fraction of patients, the methylation is present in normal tissues. It isn’t confined to the tumor. This predisposes cells to cancer development,” Hitchins said. “Because methylation is usually only present in the tumor, these patients have been automatically identified as non-Lynch patients, and never given the blood testing that would diagnose them with Lynch syndrome.”

To help determine how often this takes place, investigators reviewed data from two large retrospective population-based studies, and tested blood DNA from all mismatch repair deficient colorectal cancer patients who participated. Among patients age 55 and younger who had methylation in their tumors, 25%-75% also had methylation in their blood, meaning they had Lynch syndrome but had not been diagnosed.

In a previous study published in the journal Gynecologic Oncology, Hitchins and fellow investigators tested the blood of patients with endometrial cancer from the same patient populations. They found that approximately 30% of endometrial cancer patients had methylation in their tumors. And among those under age 50, 15%-20% also had methylation in their blood, indicating Lynch syndrome, Hitchins said.

“Taken together, these studies suggest this population of patients would benefit from a change in screening guidelines,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “Appropriate screening can provide the opportunity for potentially lifesaving surveillance and early detection and treatment of subsequent cancers.”

For now, Hitchins recommends that colorectal cancer patients under age 56 and endometrial cancer patients under age 50 ask their healthcare providers about additional screening for themselves—and their parents, siblings and adult children. She also suggested that primary care providers and oncologists reach out to young patients from the past five years whose endometrial or colorectal tumors tested positive for MLH1 methylation.

“We’ve been finding young patients with endometrial or colorectal cancer who are told they don’t have Lynch syndrome, then go on to develop a colon or other cancer that might have been prevented, or at least detected earlier,” Hitchins said. “Those patients are walking around oblivious to their risk, and should be made aware of that fact and given the option of having a test.”

Funding: This study was funded by the National Cancer Institute of the National Institutes of Health R01 grant numbers CA218342, CA67941, and CA16058; a Cedars-Sinai Medical Center Precision Health Initiative Award; Spanish Ministry of Science grants SAF2015-68016-R, and PID2019-111254RB-I00; and travel fellowship number MINECO, EEBB-I-16-11581 from the Spanish Ministry of Economy, Industry and Competitiveness, and number RD12/0036/0031 from the RTICC network.

Read more on the Cedars-Sinai Blog: Uterine Cancer—What Women Need to Know

The study, published today in the leading scientific journal Nature, found that loss of the Y chromosome helps cancer cells evade the body’s immune system. This common impact of the aging process in men results in aggressive bladder cancer, but somehow also renders the disease more vulnerable—and responsive—to a standard treatment called immune checkpoint inhibitors.

Based on their research, investigators are developing a test for loss of the Y chromosome in tumors with the goal of helping clinicians tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.

“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, the PHASE ONE Distinguished Chair and corresponding author of the publication, who initiated the research. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”

Lead collaborators on the study also included Johanna Schafer, a postdoctoral fellow, and Zihai Li, MD, PhD, medical oncologist and immunologist, both at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute.

In humans, each cell normally has one pair of sex chromosomes; men have one X and one Y chromosome, while women have two X chromosomes. In men, loss of the Y chromosome has been observed in several cancer types, including 10%-40% of bladder cancers. Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease.

The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure loss of the Y chromosome in cancers.  

The investigators then reviewed data on two groups of men. One group had muscle invasive bladder cancer and had their bladders removed, but were not treated with an immune checkpoint inhibitor. The other group participated in a clinical trial and were treated with an immune checkpoint inhibitor. They found that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.

To determine why this happens, investigators next compared growth rates of bladder cancer cells from laboratory mice.

The investigators grew cancer cells in a dish where the cells were not exposed to immune cells. The researchers also grew the diseased cells in mice that were missing a type of immune cell called T-cells. In both cases, tumors with and without the Y chromosome grew at the same rate.

In mice with intact immune systems, tumors lacking the Y chromosome grew at a much faster rate than did tumors with the intact Y chromosome.

“The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said. “These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”

Based on their results derived from human patients and laboratory mice, Theodorescu and his team also concluded that tumors missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors. This therapy, one of the two mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and allows the body’s immune system to fight the cancer.

"Fortunately, this aggressive cancer has an Achilles’ heel, in that it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” said Hany Abdel-Hafiz, PhD, associate professor at Cedars-Sinai Cancer and co-first author of the study with Schafer and Xingyu Chen, a research bioinformatician at Cedars-Sinai.

Preliminary data not yet published shows that loss of the Y chromosome also renders prostate cancers more aggressive, Theodorescu said.

“Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs,” said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs and dean of the Medical Faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”

Further work is needed to help investigators understand the genetic connection between loss of the Y chromosome and T-cell exhaustion.

“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”

While women do not have a Y chromosome, Theodorescu said these findings could have implications for them as well. The Y chromosome contains a set of related genes, called paralogue genes, on the X chromosome, and these might play a role in both women and in men. Additional research is needed to determine what that role might be.

“Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women, and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”

Funding: This work was supported in part by National Institutes of Health grant numbers P01CA278732, R01CA143971, R01CA262069, R01CA262388 and R01AI077283; an Ohio State University Comprehensive Cancer Center Tumor Immunology T32 post-doctoral fellowship award, and the Immune Monitoring and Discovery Platform and the Pelotonia Institute for Immuno-Oncology at OSU Comprehensive Cancer Center.

DOI: 10.1038/s41586-023-06234-x

Read more on the Cedars-Sinai Blog: Bladder Cancer Breakthroughs

Physicians at Cedars-Sinai Cancer are using a unique chemotherapy delivery system that offers hope to colorectal cancer patients whose disease has spread and who now have inoperable liver tumors. Cedars-Sinai is one of the few centers in the area to offer the therapy, called hepatic artery infusion (HAI) pump chemotherapy.

“Many of these patients are not candidates for curative surgery and we now have a meaningful option for treating them,” said Cristina Ferrone, MD, chair of the Department of Surgery at Cedars-Sinai and a specialist in the care of patients with complex hepato-pancreato-biliary disorders. “This therapy has been shown to extend both life and quality of life.”

Colorectal cancer is the fourth-leading cause of cancer-related death in the U.S. In as many as 25% of patients diagnosed with the disease, the cancer spreads to the liver, where it can be difficult to treat. However, more than half of patients receiving hepatic artery infusion pump therapy go on to receive curative surgery, studies have shown.

Surgical oncologist Alexandra Gangi, MD, director of the Gastrointestinal Tumor Program at Cedars-Sinai Cancer and associate professor of Surgery at Cedars-Sinai, sat down with the Cedars-Sinai Newsroom to explain this lifesaving therapy.

How do the pumps work?

We surgically place the pump underneath the skin, outside of the abdominal cavity, and it is attached to tubing that enters the abdominal cavity and goes into the gastroduodenal artery. That artery feeds into the hepatic artery, which supplies blood to the liver. During surgery, we block blood flow from the gastroduodenal artery from going into portions of the small intestine so that the therapy flows only to the liver.

The pump has a soft center, allowing its internal reservoir to be filled through the skin via a syringe. After surgery, the patient comes in every two weeks and we refill the pump, which then allows the chemotherapy drug to flow directly into the liver via the arterial supply.

Which patients are likely to benefit from hepatic artery infusion pump therapy?

This therapy is designed for patients, based on the distribution of the metastatic disease (where are the tumors and how many), for whom curative surgery is not an option at the time of diagnosis. The best we had been able to offer these patients was lifelong chemotherapy that had potential systemic toxicities, and that never quite reduced their tumor size to the point that we could surgically remove it. This therapy offers an additional option for liver-directed therapy that can potentially make patients candidates for surgery by specifically targeting the liver disease.

What are the advantages of the hepatic artery infusion pump over traditional chemotherapy delivery?

A majority of these tumors derive their blood supply from the hepatic arterial system, and delivering chemotherapy to the tumors through the hepatic arterial system allows us to give higher doses of specific chemotherapeutic agents without exposing the patient to their systemic toxicities. Data shows that up to 60% of appropriately selected patients receiving hepatic artery infusion pump chemotherapy were then able to receive curative surgery. Patients can often continue receiving systemic chemotherapy in combination with hepatic artery infusion pump chemotherapy.

Are hepatic artery infusion pumps used to treat other types of liver cancer?

Some patients with cholangiocarcinoma are currently treated with HAI pumps, but this is not yet standard of care. Colon cancer is the second most common cancer, and colon cancer that has metastasized to the liver affects a significant number of patients. And we have seen good outcomes with those patients. Other types of cancers that metastasize to the liver are significantly more challenging to treat, and thus far, we don't think this therapy will benefit those patients.

Is this a new therapy?

Hepatic artery infusion pumps have actually been around for about 25 to 30 years, but until quite recently only a few medical centers were using them. But more and more centers are realizing that this therapy can truly benefit patients, and it is becoming more widely available.

Read more from Discoveries: The Liver/Cancer Connection