Sylvester Researcher Receives NCI Grant to Study Innovative Strategy Against Pancreatic Cancer

A Sylvester Comprehensive Cancer Center researcher is testing an innovative strategy against pancreatic cancer using a combination of synthesized natural compounds and immunotherapy. Pancreatic cancer is predicted to become the second leading cause of cancer death in the United States by 2025. Current standard-of-care drug regimens have shown limited clinical efficacy and are often poorly tolerated in patients due to toxic side effects.

“There is a desperate need to develop novel therapeutic approaches in pancreatic cancer that reduce tumor burden and improve overall survival without producing significant off-target effects,” said Nagaraj Nagathihalli, Ph.D., assistant professor of surgery at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine.  “If successful, this combination will provide a rationale to scale up to clinical studies.”

Dr. Nagaraj Nagathihalli

Dr. Nagathihalli recently received a two-year grant from the National Cancer Institute entitled “Combining Immunotherapy with Urolithin A to Improve Pancreatic Cancer Survival.”  Urolithin A is a natural compound derived from pomegranates that has potent antitumor effects. The new NCI grant builds on Dr. Nagathihalli’s pre-clinical research showing that a microbial metabolite, Urolithin A, derived from a compound found in berries and pomegranates, can reduce and protect against pancreatic cancer in a laboratory model.  That study, “Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer,” was published in Molecular Cancer Therapeutics in 2019.

In that study, Dr. Nagathihalli and his team showed that Urolithin A can block tumor cell growth and improve survival in mouse models of pancreatic cancer. Interestingly, Urolithin A treatment also induced dramatic changes to the immune cell composition within tumors, suggesting that it could enhance the ability of the host immune system to fight pancreatic cancer.

“Pancreatic cancers are notorious for their ability to evade detection by the body’s immune system,” said Dr. Nagathihalli. “Our preclinical data demonstrate that Urolithin A can alter the immunologically ‘cold’ pancreatic cancer microenvironment and result in a high accumulation of reactive T cells that could indicate synergism with immunomodulatory therapies.”

“We are investigating how we can combine checkpoint inhibitors – which enhance the ability of T cells to kill the cancer cells – with Urolithin A treatment to improve survival in experimental models,” he added.

Dr. Nagathihalli is leading the research team with translational research support from Nipun Merchant, M.D., professor of surgery and chief of surgical oncology. “This project investigates the relatively unexplored immune landscape of oncogene-driven pancreatic cancer that will provide novel insights into the pathophysiology,” said Dr. Merchant.

Other project investigators are Supriya Srinivasan, Ph.D., a postdoctoral fellow, and Eli Gilboa, Ph.D., professor of microbiology and immunology. This research was facilitated by startup funding from Sylvester Comprehensive Cancer Center.

“There are a growing number of FDA-approved anticancer agents derived from naturally occurring compounds or their derivatives,” said Dr. Nagathihalli. “The preclinical models have demonstrated that Urolithin A is well tolerated and does not elicit any adverse toxic effects at clinically relevant doses. We believe this is a promising approach for addressing the challenges of pancreatic cancer. These studies will be essential in our eventual goal to scale into clinical studies in pancreatic cancer patients.”

Tags: Dr. Nagaraj Nagathihalli, pancreatic cancer, Sylvester Comprehensive Cancer Center