Things are hotting up in the prostate cancer field, with scientists discovering several new targets that may provide hope for patients with late-stage prostate cancer.
Androgens (testosterone and dihydrotestosterone) are known to fuel the growth of prostate cancers as they bind the androgen receptor (AR) driving signaling pathways that driving tumor cell proliferation and tumor development. To halt the effects of androgens binding the AR, androgen deprivation therapy (ADT) is used to try and block the levels of circulating androgens and prevent them from fuelling tumor growth.
Despite ADT reducing androgen levels to very low or ‘castrate’ levels, castrate-resistant prostate cancer (CRPC) typically develops in most patients who initially respond to treatment. The precise mechanisms underlying this resistance are just starting to be worked out, but it seems that that ADT does not fully ablate androgen synthesis in the adrenal glands (where androgen synthesis normally occurs) nor in the tumor itself where recently it has been discovered that androgen synthesis also occurs.
Once CRPC develops, the time to death is about 2 years and treatment options in this patient population are limited, demonstrating a high unmet need for treatments that prolong survival in these patients.
Androgens are synthesized from cholesterol involving complex enzymatic pathways, which includes the enzyme 3 beta-hydroxysteroid dehydrogenase which takes inactive precursors (DHEA and A5diol) and converts them to the more active androgens, androstenedione and testosterone, which are later converted to dihydrotestosterone. If this enzyme is active in prostate tumors, testosterone and dihydrotestosterone could in theory bind the AR and continue to fuel tumor growth. In a recent study in the journal Endocrinology, Evaul et al., discovered that was the case with 3 beta-hydroxysteroid dehydrogenase being necessary for producing testosterone and dihydrotestosterone in models of CRPC, which then activates the AR, driving tumor cell proliferation. As a result, this enzyme is thought to provide an attractive new target for the treatment of CRPC.
At the moment this is just a hypothesis that needs to be tested in the clinic. However, there are similar agents currently in later stages of development, including abiraterone and TAK700 which inhibit another enzyme in the androgen synthesis pathway (CYP17,20), MDV3100 which blocks androgens binding the AR, and VN/124-1 which both inhibits CYP17,20 and blocks androgens binding the AR. These are indeed exciting times for prostate cancer patients.