A MAO inhibitor drug called phenelzine represents a potential new treatment direction with fewer side effects for men with recurrent prostate cancer, researchers said. "To our knowledge, this study is the first clinical trial of an MAO inhibitor in cancer patients," said senior author Jean Shih, a professor in the University of Southern California School of Pharmacy who has studied the enzyme MAO, or monoamine oxidase, for four decades.
"If our findings are confirmed, this could be part of a new avenue for patients that could avoid undesirable side effects of standard therapies," said first author Mitchell Gross, a medical oncologist and research director at the Lawrence J Ellison Institute for Transformative Medicine of USC. Gross and Shih have been collaborating for several years to bring her research out of the lab and into the clinic.
In this study, 11 of 20 participants had a measurable decline in their PSA levels after 12 weeks of twice-a-day treatment, with the greatest decline in PSA being a 74% drop. PSA stands for prostate specific antigen; it's a biomarker for prostate cancer circulating in the blood.
Prostate cancer is the second most common cancer – behind skin cancer – diagnosed in men in the US, with about 174,000 cases diagnosed each year. For most patients, prostate cancer is treated with surgery or radiation or a combination of the two.
After surgery, a patient's PSA should be close to zero. However, in about one-third of patients, the PSA level rises again, indicating the cancer has returned. Hormone therapy is a standard treatment for recurrent prostate cancer, but it comes with serious side effects that impact quality of life. That's where MAO inhibitors may be able to help.
MAO inhibitors treat depression by readjusting levels of neurotransmitters such as serotonin and dopamine in the brain. The downside is that the medication requires dietary changes and careful avoidance of drug interactions to prevent serious side effects.
In prostate cancer, MAO inhibitors disrupt androgen receptor signalling – the main growth pathway for prostate cancer. Previous studies with animals and human prostate cancer cell lines showed that MAO inhibitors decreased the growth and spread of prostate cancer, the researchers found.
Because the MAO inhibitor phenelzine is already FDA-approved, the researchers were able to rapidly design and implement a pilot study to test the drug's ability to fight cancer.
For this study, researchers enrolled 20 participants who had been treated for prostate cancer and who had elevated PSA levels. Patients received the MAO inhibitor phenelzine twice a day for 12 weeks – 55% of the men experienced PSA declines; five of them saw PSA level declines of 30% or more; two participants saw decreases of 50% or more.
Three patients had to drop out due to dizziness or hypertension.
The main limitations of the study include the lack of a placebo comparison group and the small sample size, researchers said. Additional studies are planned, and Shih has patented a second-generation MAO inhibitor tagged with a substance that could help doctors see where the cancer has spread.
Abstract
Purpose: Monoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer.
Materials and methods: An open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by PSA ≥ 0.4 ng/ml (post prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline.
Results: Characteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥30% and ≥50% were observed in 25% (n = 5/20) and 10% (n = 2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥30% and ≥50% of 24% (n = 4/17) and 6% (n = 1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2 = 35%), hypertension (grade ≥ 2 = 30%), and edema (grade 1 = 25%, grade 2 = 10%). There was one episode of grade 4 hypertension (cycle 4) and two episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment.
Conclusions: Phenelzine demonstrated efficacy in patients with biochemical recurrent castrate-sensitive prostate cancer. Most treatment-related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer.
Authors
Mitchell E Gross, David B Agus, Tanya B Dorff, Jacek K Pinski, David I Quinn, Olga Castellanos, Patrick Gilmore, Jean C Shih
[link url="https://news.usc.edu/166277/antidepressant-prostate-cancer-mao-inhibitor-phenelzine/"]University of Southern California material[/link]
[link url="https://www.nature.com/articles/s41391-020-0211-9"]Prostate Cancer and Prostatic Diseases abstract[/link]