Research Tip Sheet: Zombie Cells, GLP-1RAs, Heart Surgery and Breast Cancer

Preclinical Study Targets ‘Zombie’ Cells

Senolytics—a class of drugs that reduce chronic inflammation and tissue damage in aging cells—are shown to eliminate 30% to 70% of “zombie” cells in the body. These zombie cells, known as senescent cells, stop dividing and don’t die, ultimately contributing to a host of diseases of aging, including cancer.

A preclinical study from Cedars-Sinai, published in Aging Cell, had three key findings:

• Senolytic drugs purge the most harmful cells, leaving less-harmful senescent cells behind.
• These remaining “senolytic-resistant” senescent cells can be activated into tissue-damaging senescent cells by infections and other factors in the environment of senescent cells.
• A new class of drugs, “senosensitizers,” can enable senolytics to eliminate these lurking senolytic-resistant “ticking time bomb” cells.

Investigators found that in laboratory mice treated with senolytic drugs, the remaining senescent cells were less inflammatory and damaging than the cells removed by the treatment. Researchers also found that these remaining senescent cells, when activated into tissue-damaging cells by an inflammatory environment, become more vulnerable to senolytics than those in a stable environment.

Based on their findings that infections can make senescent cells become susceptible to senolytics, study authors theorize that targeting senescent cells with newly developed senosensitizers—and then senolytics—might allow more senescent cells to be removed than when using senolytics alone. This could remove senolytic-resistant senescent cells and reduce the impact of infections in previously apparently healthy older people.

“This drug combination, which is still in the preclinical phase, has the potential to target senescent cancer cells that persist after radiation and chemotherapy and may later reemerge as more aggressive disease,” said James Kirkland, MD, PhD, director of the Center for Advanced Gerotherapeutics and senior author of the study.

Additional Cedars-Sinai authors include Masayoshi Suda, Tamar Tchkonia, Selim Chaib, Larissa Langhi Prata, Tamar Pirtskhalava and Nino Giorgadze.

Additional authors include Utkarsh Tripathi, Vagisha Kulshreshtha, Bryan T. Piatkowski, Allyson K. Palmer, Christina Inman, Nathan Gasek, Ming Xu, Kurt O. Johnson, Yi Zhu, Renuka Kandhaya-Pillai, Stefan G. Tullius, Saranya P. Wyles, Rambabu Majji, Hari Krishna Yalamanchili and David B. Allison.

Funding: This work was supported by NIH grants R37AG013925 (J.L.K., T.T.), R33AG061456 (J.L.K., T.T.), R01AG066679 (M.X.), R01AG076642 (M.X.), R01AG064165 (S.G.T.), R01AG087387 (Y.Z.), the Connor Fund (J.L.K., T.T.), Robert J. and Theresa W. Ryan (J.L.K., T.T.), HF-GRO-­23-­ 1199148-­ 3 (J.L.K.), HF-­ GRO-­ 23-­ 1199262-­ 27 (Y.Z., M.S.), the JSPS Grants-­ in-­ Aid for Scientific Research Fund for the Promotion of Joint International Research (Fostering Joint International Research) 23KK0295 (M.S.), the Yamada Science Foundation (M.S.), and USDA/ARS grant CRIS 3092-­ 51000-­ 065-­ 003S (H.K.Y.) and the Noaber Foundation (J.L.K.). U.T. was supported by an American Heart Association predoctoral fellowship (917775).

Cedars-Sinai Study Links GLP-1RA Drugs to Risk of Chronic Cough

Patients who take the widely used Type 2 diabetes and obesity medications known as glucagon-like peptide-1 receptor agonists (GLP-1RAs) appear to be at increased risk of developing chronic cough, according to a new multicenter study led by Cedars-Sinai and published in JAMA Otolaryngology – Head & Neck Surgery.

GLP-1RA medications, marketed under many brand names, work by stimulating insulin release from the pancreas, lowering blood sugar and slowing digestion. As a result, these drugs may help people with Type 2 diabetes manage their blood sugar and help people with obesity lose weight.

Investigators reviewed 10 years of electronic medical records with data on more than 2 million Type 2 diabetes patients at 70 healthcare organizations. They compared records of individuals prescribed a GLP-1RA drug with those who were prescribed a non-GLP-1RA drug to treat diabetes, and found that GLP-1RA use was associated with a significantly increased risk of new chronic cough.

“Further research is needed to confirm the existence, strength and mechanisms of the association between GLP-1RA drugs and chronic cough,” said Anca Barbu, MD, associate professor in the Jim and Eleanor Randall Department of Surgery and the study’s corresponding author. “However, our findings highlight the importance of physicians and care providers asking patients with new-onset chronic cough about possible GLP-1RA use, and for healthcare providers prescribing these medications to discuss chronic cough as a possible side effect.”

The other Cedars-Sinai author is Neelaysh Vukkadala, MD.

Additional authors include Tyler J. Gallagher, MD, MPH; Diego E. Razura, MD; Albert Li, BA; and Ian Kim, PhD. 

Bodily Fluid Changes Linked to Poor Heart Surgery Outcomes

Patients who lose or gain a significant amount of fluid after certain elective heart surgeries are more likely to be readmitted to the ICU, stay longer in the hospital or die than patients whose fluid levels remain stable, according to a new study from Cedars-Sinai. The findings, published in Anesthesia & Analgesia, could help improve patient care.

Investigators reviewed data on 2,557 patients who underwent nonemergency coronary artery bypass grafts, valve surgeries or a combination of the two. They calculated each patient’s total fluid intake (including oral and intravenous fluids and blood products) and output (including urine, stool and surgical drains), based on measurements taken in the operating room and in the ICU after surgery.

“It remains unclear whether changes in cumulative fluid balances above 1.5 liters on the day of ICU discharge actually cause adverse outcomes or are just associated with them,” said senior author Joseph Ebinger, MD, MS, associate professor of Cardiology and director of the Coronary Intensive Care Unit and Clinical Analytics in the Smidt Heart Institute at Cedars-Sinai. “Further study is called for. In the meantime, our findings suggest that greater attention to such variations may help improve outcomes for cardiac surgery patients.”

Other Cedars-Sinai authors are Abirami Kumaresan, George Gill, Jesse Navarrette, Tao Shen, Milad Sharifpour, Dominic Emerson, Joanna Chikwe and Susan Cheng.

Funding: This study was supported in part by a grant from the International Anesthesia Research Society and NIH grant: K23-HL153888. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Different Immune Cell Types Correlate with Breast Cancer Survival

The quantities of specific types of immune cells that appear in and around a breast cancer tumor are correlated with the prognosis for the patient, according to a new study led by Cedars-Sinai. The findings have implications for use of immunotherapy in this disease, the second leading cause of cancer deaths among women in the U.S.

The study was published in the peer-reviewed journal iScience.

Investigators analyzed images from 12,285 female breast cancers, including estrogen-positive breast cancer, the most common type, in which cancer cells have a protein that binds to the hormone estrogen; estrogen-negative breast cancer, in which the cells lack this protein, was also studied.

Using artificial intelligence (AI), investigators calculated the percentages of different types of immune cells within the tumors, in nearby connective tissue (known as stroma) and in total for both areas. They examined the relationship between these percentages and the likelihood that the patient would die from breast cancer over a certain period of time after diagnosis. Two types of immune cells, CD8+ and CD20+, were found to be associated with a better prognosis in estrogen-positive breast cancer patients, whereas another cell type, CD163+, was associated with a poorer prognosis. CD8+ and FOXP3+ immune cells were associated with a better prognosis in estrogen-negative breast cancer.

“Our findings suggest that the immune system is an important predictor of outcome in hormone-positive breast cancer,” said Paul Pharoah, MD, PhD, professor of cancer epidemiology in the Department of Computational Biomedicine at Cedars-Sinai and the study’s senior and corresponding author. “They support including this subset of patients in clinical trials of immune modulators, which could lead to improved treatments for women with this common cancer.”

Other authors include: Aaron J. Bernstein PhD, Renske Keeman MSc, Amber Hurson PhD, Fiona M. Blows PhD, Manjeet K. Bolla MSc, Jodi L. Miller PhD, Roger L. Milne PhD, Hugo Horlings MD, PhD, Alexandra J. van den Broek PhD, Clara Bodelon PhD, James M. Hodge JD, MPH, Alpa V. Patel PhD, Lauren R. Teras PhD, Federico Canzian PhD, Rudolf Kaaks PhD, Hermann Brenner MD, Ben Schöttker PhD, Sabine Behrens PhD, Jenny Chang-Claude PhD, Tabea Maurer DiplPsych, Nadia Obi PhD, Fergus J. Couch PhD1, H. Raza Ali PhD, Carlos Caldas MD, Irene Andrulis PhD, Gord Glendon MSc, Anna Marie Mulligan MD, Wilma Mesker PhD, Agnes Jager MD, PhD, Annette Heemskerk-Gerritsen PhD, Peter Devilee PhD, Scott M. Lawrence PhD, Jolanta Lissowska PhD, Karun Mutreja PhD, Thomas Ahearn PhD, Stephen Chanock MD, Maire A. Duggan MD, Diana Eccles PhD, J. Louise Jones MB ChB, PhD, Will Tapper PhD, Antoinette Hollestelle PhD, Maartje Hooning PhD, John Martens PhD, Carolien H.M. van Deurzen MD, PhD, Angela Cox PhD3, Simon S. Cross MB BS, Mikael Hartman MD, PhD, Jingmei Li PhD, Thomas C. Putti MD, Ute Hamann PhD, Muhammad Rashid MB BS, PhD, Ania Jakubowska PhD, Nicki Camp PhD, Melissa H. Cessna MD, Amy Berrington de Gonzalez DPhil, Katarzyna Bialkowska PhD, Jacek Gronwald PhD, Jan Lubiński MD, PhD, Siddhartha Yadav MD, Pietro Lio PhD, Doug F. Easton PhD, Mustapha Abubakar MD, PhD, Montse Garcia-Closas MD, DrPH,  and Marjanka K. Schmidt, PhD.

Acknowledgements: The authors thank the Histology and Genomics Cores at the Cancer Research UK Cambridge Institute for technical support, and all patients, researchers, clinicians, and administrative personnel who contributed to the studies taking part in BCAST.  The CPSII study investigators acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention's National Program of Cancer Registries and cancer registries supported by the National Cancer Institute's Surveillance Epidemiology and End Results Program.

BCAC was supported by Cancer Research UK grant: PPRPGMNov20\100002 and by core funding from the NIHR Cambridge Biomedical Research Centre (NIHR203312). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.  The BCAST project was supported by the Horizon 2020 Research and Innovation Programs of the European Union B (grant number: 633784) and the NIHR Cambridge Biomedical Research Centre. AJB was supported by the NIH Oxford-Cambridge Scholars and Gates Cambridge Scholars programs. (The funding of the contributing studies is listed in a supplementary table in the article.)

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