Seven-Year Prostate Cancer Project Reaches Drug Discovery Phase

With support from a new Department of Defense grant, Drs. Sharifi and Stauffer will continue work on a promising prostate cancer drug target, which has already reached in vivo proof of concept studies.

04/03/2020

The Department of Defense’s Prostate Cancer Research Program has awarded Nima Sharifi, MD, who directs the Cleveland Clinic Genitourinary Malignancies Research Center, a three-year, $1.2 million Translational Science Award to support a prostate cancer drug development project.

A look back at the project’s early beginnings

In 2013, Dr. Sharifi made the paradigm-shifting discovery that a common genetic variant—HSD3B1(1245C)—helps prostate cancer cells evade androgen deprivation therapy, the first line treatment defense against prostate cancer, by enabling the cells to produce their own “fuel” (hormones called androgens).

More recently, in a landmark clinical trial validation study published earlier this year, he and his team showed that men who inherited this variant more quickly developed treatment-resistant cancer and had shorter overall survival. On the study’s significance, Dr. Sharifi said it makes the case for potentially incorporating clinical genotyping as part of routine care for prostate cancer patients, where HSD3B1(1245C) inheritance indicates that a more upfront or aggressive treatment approach is necessary.

Where are they now?

The new DOD Translational Science Award will enable Dr. Sharifi and his collaborator, Shaun Stauffer, PhD, director of the Cleveland Clinic Center for Therapeutics Discovery, to continue this line of investigation into how an individual patient’s genetics can guide clinicians in treatment decision-making.

Currently, knowledge that a patient has the variant may help clinicians to decide which of the four existing prostate cancer drugs is best to prescribe in conjunction with androgen deprivation therapy. But Drs. Sharifi and Stauffer also think it could inform which patients are ideal candidates for a yet-to-be-developed drug—one that uniquely acts on the variant itself, blocking the metabolic machinery that enables cancer cells to produce their own disease-fueling androgens.

The two have been working together for nearly two years on such a compound. During that time, they have identified a promising drug target—the metabolic enzyme produced by the 1245C variant, 3βHSD1—and are currently conducting in vivo proof of concept validation studies. The new Translational Science Award will provide critical support as they continue to usher this target through the rest of the drug development pipeline—which, they believe, could happen in as few as three years.

The team’s other drug discovery projects

This Department of Defense award is just the latest for Drs. Sharifi and Stauffer together. Back in 2018, Dr. Sharifi received a $1 million award from the Prostate Cancer Foundation to interrogate a different drug target—a pathway that causes prostate cancer cells to accumulate more of the stress hormone cortisol, which enables tumors to withstand treatment and continue to thrive.

As all of Dr. Sharifi’s research has suggested, prostate cancer is a dynamic disease, and one that may not be cured with a single magic bullet. As evidenced by the team’s multiple and diverse drug discovery projects, Dr. Sharifi continues to move forward looking to attack prostate cancer from many fronts.



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