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.

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counters previous research suggesting that Black men receiving these therapies—which include hormone therapy, chemotherapy and immunotherapy—fare worse than white men do.

“We believe this is the most comprehensive look at this issue to date, and our findings suggest that, under the right conditions, Black men with metastatic prostate cancer can have outcomes equivalent to those of white men,” said Jun Gong, MD, medical director of Colorectal Cancer Medicine at Cedars-Sinai Cancer and first author of the study. “We want all men with advanced prostate cancer to know that, in the right environment, their outcomes can be promising.”

Prostate cancer, which affects the small gland that helps make semen, is the No. 1 cancer diagnosis and second-leading cause of cancer death in Black men. Black men are twice as likely as white men to die of prostate cancer, a fact that has been at least partially attributed to systemic barriers to healthcare for Black men.

Investigators in this study contrasted data from a large database of cancer registries reporting outcomes in all types of healthcare settings with two other types of data. One set of data was collected in healthcare settings including the Department of Veteran’s Affairs, where access to care for Black patients and white is more equal. Another set of data was from randomized clinical trials where all prostate cancer patients received the same treatment, and outcomes for Black versus white patients were compared.

“It was interesting to find that when Black and white men were provided equal access to the same therapies, given at the same dosage and monitored in the same setting, disparities in outcomes were eliminated,” Gong said.

Gong said that the team’s findings point to the need for continued active recruitment of Black men and other minority groups into prostate cancer clinical trials. Community outreach and education are also needed, along with other efforts to provide more equal-access settings for prostate cancer patients.

“Addressing disparities affecting the health of the diverse populations we serve is a priority throughout our institution,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “Through our Community Outreach and Engagement efforts and our ongoing research, we are working to better understand the factors contributing to these disparities, including socioeconomic factors and biological drivers that can be addressed through continued advances in precision medicine.”

Gong and his colleagues have additional studies underway to further explore these issues. One is examining treatment patterns for Black versus white prostate cancer patients within the VA, including type of therapy offered, time from diagnosis to initiation of treatment, and what happens when these factors are equalized.

A separate study is examining drug compliance in Black versus white metastatic prostate cancer patients, how that affects patient outcomes, and whether Black men fare as well as white men when patient compliance is equal.

Funding: This work was supported by a Prostate Cancer Foundation Young Investigator Award, Department of Defense Health Disparity Research Award number W81XWH-19-1-0748, and American Cancer Society Research Scholar Grant number RSG-18-018-01-CPHPS.

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