Cover image: illustration of prostate cancer cells (iStock by Getty Images)
Researchers at the Lawrence J. Ellison Institute for Transformative Medicine of USC and the USC School of Pharmacy have conducted the first published clinical trial showing that a decades-old antidepressant may have the potential to fend off prostate cancer recurrence.
The clinical trial, led by Mitchell Gross, MD, PhD of the Ellison Institute and the Keck School of Medicine of USC and Jean Shih, PhD of the USC School of Pharmacy, focused on patients requiring follow-up treatment to prevent prostate cancer recurrence after initial therapy. The study showed that the antidepressant phenelzine lowered levels of prostate-specific antigen (PSA), a key marker used to monitor prostate cancer. The drug may also improve patients’ moods as well. Based on these promising preliminary results, the team plans to further explore how phenelzine may be used in combination with traditional therapies to prevent metastatic cancer down the road.
The researchers report the results of their phase II clinical trial today in the journal Prostate Cancer and Prostatic Diseases.
Tracking the molecular footprints of cancer after therapy
Prostate cancer is the most common male cancer in the United States, excluding skin cancer, with approximately 175,000 new cases diagnosed each year. While the majority of cases are effectively treated with surgery or radiation, cancer recurs in as many as one-third of patients. Recurrence is most often detected by blood tests used to routinely monitor patients who have undergone treatment involving surgery, radiation, or hormone-based therapies.
Biochemical recurrence occurs when doctors only detect signs of lingering disease through laboratory tests, despite no visible tumors on a patient’s scans. In these cases, blood tests still register clinically detectable levels of PSA –– a protein produced only by prostate cells –– even after the prostate gland has been surgically removed. Detectable PSA after prostate removal likely indicates that a patient has small quantities of metastatic prostate cancer cells dispersed throughout the body, which are producing the PSA. Doctors worry that those covert cells will eventually sprout metastatic tumors months or years down the road.
The current standard treatment for patients with biochemical recurrence is an approach called androgen deprivation therapy, which lowers the levels of male hormones known as androgens. Prostate cancer often requires androgens to survive and grow, so the hope is that starving the body of male hormones will prevent metastatic tumors from growing. This approach, however, is plagued by undesirable side effects ranging from mood swings and fatigue to loss of bone density and growth of breast tissue in some cases. There is currently little consensus regarding when doctors should prescribe androgen deprivation therapy to treat biochemical recurrence, versus simply monitoring the patient over time.
An old drug with a new purpose
Gross and Shih set out to improve the treatment landscape for patients with biochemical recurrence by combining Shih’s 30 years of seminal pharmaceutical research with Gross’ extensive clinical knowledge and experience treating prostate cancer.
They targeted an enzyme known as monoamine oxidase A (MAOA), which breaks down hormones and neurotransmitters like dopamine, serotonin and norepinephrine, and is widely known for its role in mood disorders like depression. Shih and Gross previously published a paper together demonstrating that inhibiting MAOA could combat prostate cancer growth in the lab. They next sought to translate these laboratory findings to clinical applications.
Drugs targeting MAOA and similar enzymes in its class are readily available on the market and are generally considered safe for the treatment of depression. After studying one of these antidepressants, phenelzine, in pre-clinical models, Shih, Gross and their team decided to repurpose the drug in prostate cancer treatment to see if it could help combat biochemical recurrence.
“As a physician-scientist, seeing all of that research on a widely available drug and knowing I could apply it to a cancer patient right away was very special and unique,” Gross said.
The results of their clinical trial showed that phenelzine was generally well-tolerated and reduced PSA levels in 55% of patients with non-metastatic, biochemically recurrent prostate cancer. These results are promising because lower PSA levels likely indicate that phenelzine exerts an anti-cancer effect and could potentially help reduce a patient’s risk of metastatic prostate cancer in the future.
“We’re happy to be able to translate our discoveries in basic research to clinical applications,” said Shih, who holds the Boyd P. and Elsie D. Welin Professorship in Pharmaceutical Sciences and serves as director of the Center for USC-Taiwan Translational Research.
“I think this effect wasn’t noticed before because phenelzine was developed in the 1960s when PSA tests hadn’t yet been invented,” Gross explained. “It was a different treatment landscape back then, so it was novel to be able to go back and find this result today.”
The research team plans on further monitoring patients for signs of metastatic disease and investigating how phenelzine works to combat prostate cancer at a molecular level.
“We’d really like to learn who responds and who doesn’t to the drug,” Gross said. Phenelzine targets both MAOA and its analog MAOB, so doctors should be able to test prostate cancer patients for those known biomarkers to determine if phenelzine treatment might be effective.
An added advantage of using a drug like phenelzine is that it falls into a completely different drug class than other cancer treatments. Doctors would not need to worry about a phenomenon known as additive toxicity, in which two similar drugs compound each other’s side effects and ultimately harm the patient. “We really believe that this drug can work with other treatments,” Gross added. “We’d like to determine what treatments it could work with and how that could benefit many more patients.”
This study was funded by the USC-Taiwan Center for Translational Research supported by the Tsai Family Fund and the National Cancer Institute Shared Grant award P30CA014089.
In addition to Shih and Gross, other authors are David Agus, MD, of the Lawrence J Ellison Institute for Transformative Medicine of USC, the USC Norris Comprehensive Cancer Center and the Department of Medicine at the Keck School of Medicine of USC; Tanya B. Dorff, Jacek K. Pinski, and David I. Quinn of the Department of Medicine and Department of Integrative Anatomical Sciences at USC; and Olga Castellanos and Patrick Gilmore of the Lawrence J. Ellison Institute for Transformative Medicine of USC.