Researcher Receives Renewed Federal Grant to Develop Next-Generation Prostate Cancer Treatments

The National Cancer Institute, part of the National Institutes of Health, has awarded a competitive renewal grant of $2.26 million to Ramesh Narayanan, PhD, professor and Muirhead Chair of Excellence in the Department of Medicine at the University of Tennessee Health Sciences. Dr. Narayanan also serves as deputy director of UT Health Sciences' Center for Cancer Research and associate dean of Research in the College of Medicine. The grant renews a five-year award originally funded from 2018 to 2023 and will support his project, "Novel Degraders of the Androgen Receptor (AR) and AR Splice Variants (AR-SVs)."

Prostate cancer ranks among the most common and deadly cancers affecting men worldwide. In the United States alone, it claims more than 30,000 lives each year, a toll that experts project will grow dramatically as the global population ages. By 2040, an estimated 3 million men are expected to receive a prostate cancer diagnosis annually, with roughly 700,000 deaths projected worldwide each year. Initial treatments typically work by cutting off the cancer's supply of male hormones, essentially starving it of the fuel it needs to grow. However, in many patients the cancer eventually finds ways to survive and spread even without that hormonal fuel. This drug-resistant form, known as castration-resistant prostate cancer, is responsible for the vast majority of prostate cancer deaths.

At the heart of the problem is a protein called the androgen receptor, which acts like an "on switch" for prostate cancer cell growth. Nearly all prostate cancers rely on this switch, making it the most important target for treatment. Current drugs work by blocking this switch, but cancer cells are remarkably adaptable. Over time they develop workarounds: producing their own fuel internally, creating altered versions of the switch that are harder to block, or activating entirely different switches to keep growing.

Developing the Triple-Threat Solution

Dr. Narayanan's laboratory, in collaboration with Dr. Duane Miller's laboratory, has already made significant progress on this challenge. Their team developed ONCT-534, currently in clinical trials, which addresses most of these resistance strategies. However, one escape route remains: cancer cells can activate a related protein called the glucocorticoid receptor (GR) as a backup switch. No current clinical candidates (including ONCT-534) are able to block this backup.

With this new funding, Dr. Narayanan's team will build on the discovery of a class of experimental molecules dubbed "triple inhibitors" that can do three things at once: destroy the primary androgen receptor switch, eliminate altered versions of that switch, and block the GR backup. Early laboratory results show these molecules are highly potent, but they currently break down too quickly inside the body to be useful as medicines. The research will systematically test and refine 50-70 variations of these molecules to find versions that are both highly effective and stable enough for the body to use. Over the five-year grant period, the team aims to identify at least one lead drug candidate ready for advanced preclinical and eventual clinical testing.

"ONCT-534, which was developed during the first five years of funding, is currently showing remarkable success in patients diagnosed with relapsed, refractory castration-resistant prostate cancer," Dr. Narayanan said. "However, we must be ready to treat resistance emerging through glucocorticoid receptor. Thanks to National Cancer Institute funding we will make the next-generation drug available to the American men and men around the world diagnosed with this aggressive form of prostate cancer."

A Merit-Based Milestone

The project is organized around three research goals: understanding the biological mechanisms that allow prostate cancer cells to develop resistance to current treatments; optimizing the chemical structure of the triple inhibitor molecules for maximum effectiveness and drug-like stability; and confirming that the best candidates work as expected in animal models before advancing toward human trials.

The competitive nature of this renewal, awarded based on merit following rigorous peer review, reflects the quality of Dr. Narayanan's prior work and the scientific community's recognition of the unmet need in treating drug-resistant prostate cancer.