Abiraterone is a CYP17 inhibitor that reduces circulating and intratumoral androgens, “decreasing the available ligand for the AR, which is testosterone or DHT. This comes from the testicles, as well as other sources such as the adrenal glands and tumors themselves,” said Dr Tagawa.
Increasing intratumoral androgen production could, however, overcome the therapeutic concentration of abiraterone, particularly if androgen synthesis occurred by a mechanism other than CYP17.
Some data suggest that AKR1C3 converts dehydroepiandrosterone (DHEAS), an androgen precursor, to testosterone and DHT.2 In vitro studies demonstrate that AKR1C3 overexpression was associated with abiraterone resistance, and downregulation of AKR1C3 presensitized prostate cancer cells to abiraterone. Treatment with indomethacin, an AK41C3 inhibitor, overcame abiraterone resistance in vitro and in animal models.2
Early clinical trials demonstrated disappointing results, however, with no clinically meaningful single-agent activity with an AKR1C3 inhibitor among men with mCRPC who progressed after chemotherapy.4 An AKR1C3 inhibitor has not been tested in addition to abiraterone in men with abiraterone-resistant mCRPC.
Androgen precursors can also be converted by 3ßHSD to testosterone and DHT, and a gain-of-function mutation was demonstrated to increase HDT production.3 Androgen production by 3ßHSD can theoretically continue despite CYP17 inhibition by abiraterone. There are, however, no clinical studies with 3ßHSD inhibitors in mCRPC.
More studies are needed to further define the role of intratumoral androgen production and mCRPC resistance to hormonal therapies, and to determine if inhibitors of other steroidogenesis enzymes can be synergistic with abiraterone.
A challenge in studying intratumoral androgen production is that “there is no current standard way to detect androgen production by individual tumor cells if it is not enough to detect in the blood. It may be possible through molecular imaging if there is sufficient signal, but this is not standard,” Dr Tagawa commented.
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“The best studies at this point are still tissue studies,” Dr Tagawa said of intratumoral androgen production, “but additional molecular imaging techniques could be a step forward.”
- Galletti G, Leach BI, Lam L, Tagawa ST. Mechanisms of resistance to systemic therapy in metastatic castration-resistant prostate cancer. Cancer Treat Rev. 2017 May 8. doi: 10.1016/j.ctrv.2017.04.008 [Epub ahead of print]
- Liu C, Armstrong CM, Lou W, Lombard A, Evans CP, Gao AC. Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer. Mol Cancer Ther. 2017;16:35-44. doi: 10.1158/1535-7163.MCT-16-0186
- Schweizer MT, Yu EY. Targeting intratumoral androgens: statins and beyond. Ther Adv Med Oncol. 2016;8:388-95. doi: 10.1177/1758834016647962
- Loriot Y, Fizazi K, Jones RJ, et al. Safety, tolerability and anti-tumor activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multicentre phase I/II study. Invest New Drugs. 2014;32:995-1004. doi: 10.1007/s10637-014-0101-x