Though the number of available therapies has increased during recent years, men with metastatic castration-resistant prostate cancer (mCRPC) inevitably have disease progression due to acquired resistance to treatment.

“By understanding mechanisms of resistance to our current therapies, we will be better able to develop new strategies to combat resistance and improve quantity and quality of life,” Scott Tagawa, MD, MS, of Weill Cornell Medicine in New York, New York told Cancer Therapy Advisor. “This may come from new drugs, new combinations of existing drugs, or better biomarkers.”

CRPC develops when prostate cancer progresses despite castrate-levels of testosterone, which may be explained by continued androgen receptor (AR) signaling driving tumor growth.

There are multiple mechanisms that can promote AR signaling, including AR splice variants, AR amplification or overexpression, AR stabilization, overexpressed transcription factors, AR mutations, and alternate signaling pathways.

None of these mechanisms are possible, however, without continued androgen production, such as by intratumoral steroidogenesis.1

Intratumoral Steroidogenesis

“We know that men with undetectable serum levels of testosterone can have cancer growth and abiraterone can be effective in men with progressive cancer despite no detectable serum testosterone,” said Dr Tagawa, suggesting that another source of testosterone is promoting tumor growth.

Studies indicate that even after androgen-deprivation therapy (ADT) intratumoral androgen synthesis can reactivate the AR. Testosterone and dihydrotestosterone (DHT) are synthesized from weak androgens produced by the adrenal glands, as well as de novo synthesis from cholesterol, within the tumor.1

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This is consistent with studies demonstrating higher levels of intratumoral androgens among men with mCRPC compared with men with primary prostate cancer. Higher intratumoral expression of CYP17A1, AKR1C3, and 3ßHSD — enzymes involved in androgen synthesis — is also associated with intratumoral androgen levels.