The progression of prostate cancer is reliant on androgens. Although androgen deprivation therapy and abiraterone eliminate the generation of androgen, disease progression is still inevitable. In a new mouse study, researchers performed a mass spectrometry-based metabolite screening of plasma samples from patients receiving androgen deprivation therapy (ADT) and abiraterone treatment. Their findings revealed the oncometabolite role of progesterone in advanced prostate cancer and strategies to eliminate its oncogenic effect.

Their findings are published in the journal Cell Reports Medicine in a paper titled,  “Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer,” and led by led by Zhenfei Li, PhD, of the CAS Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences.

“Prostate cancer continuously progresses following deprivation of circulating androgens originating from the testis and adrenal glands, indicating the existence of oncometabolites beyond androgens,” the researchers wrote. “In this study, mass spectrometry-based screening of clinical specimens and a retrospective analysis on the clinical data of prostate cancer patients indicate the potential oncogenic effects of progesterone in patients.”

The researchers investigated alteration in the metabolomics of abiraterone-resistant patients and found that one metabolite—progesterone—increased significantly. Transient treatment with high doses of progesterone will activate multiple pathways to promote the proliferation of cancer cells. Long-term treatment with progesterone at a low dosage will increase the expression of GATA2, resulting in an irreversible alteration in the transcriptome that promotes disease progression.

They also investigated the metabolic pathway of progesterone and identified the enzyme 3βHSD1 as a potential therapeutic target for eliminating the generation of progesterone.

Their findings suggest progesterone might be a potential predictive biomarker for abiraterone response and related clinical research is in progress.

“In summary, this work identified progesterone as an oncogenic hormone in prostate cancer patients receiving abiraterone treatment,” concluded the researchers. “BCA was discovered as a potent 3βHSD1 inhibitor and prevented the oncogenic effects of progesterone by suppressing the synthesis of progesterone. Higher plasma levels of progesterone are correlated with poor clinical outcomes of abiraterone treatment in patients.”