Gregory Wilson

Introduction: Prostate cancer is the second most diagnosed cancer among males and the sixth most common cause of death of men in the world². While first line therapies, including androgen deprivation therapy, are effective treatments for most patients, some suffer a progression of the disease to castration resistant prostate cancer (CRPC), which is less responsive to therapy and has a poor prognosis. One factor contributing to the progression of CRPC is the intratumoral conversion of adrenal androgens into gonadal androgens via the backdoor and alternative pathways mediated by CYP17A1 enzyme^1,5. Other research shows that upregulation and increased sensitivity of the androgen receptor may contribute to CRPC progression^4,6. Understanding the mechanisms that contribute to the progression of a tumor from a castration sensitive to a castration resistant form may lead to the development of novel therapeutics for this disease. Methods: Groups of castrated mice were used to model tissue responses to CYP17A1 inhibition vs complete adrenalectomy. LuCaP35CR and LuCaP96CR cell lines were used to generate xenografts to induce tumorigenesis in mice. Randomized groups of mice that suffered a progression to CRPC were selected to undergo adrenalectomy. The overall tumor growth from these mice was compared to mice with CRPC treated with a CYP17A1 inhibitor alone rather than adrenalectomy³. Results: Mice that underwent complete adrenalectomy had significantly smaller tumors and lower serum levels of gonadal androgens compared to mice treated with CYP17A1 inhibitors³. Mice carrying CRPC exhibit an upregulation of LRH-1 four days following castration⁶, which correlates with an overexpression of the androgen receptor. A clinical study showed that androgen receptor upregulation is the single most predictive factor of progression to CRPC⁴. Additionally, patients with CRPC carry androgen receptors that are much more sensitive and may be activated by a larger number of substrates than the typical androgen receptor⁴. Conclusions: Studies have begun to clarify a few mechanisms whereby prostate cancer progresses to CRPC. Further investigation of the alternative and backdoor pathways may lead to the identification of enzymes or receptors that could be therapeutically targeted to slow or inhibit intratumoral androgen synthesis. Understanding what factors lead to upregulation and over sensitization of the androgen receptor could also provide important details on disease progression and lead to the development of improved treatments.

1. Barnard L, Gent R, van Rooyen D, Swart AC. Adrenal C11-oxy C₂₁ steroids contribute to the C11-oxy C₁₉ steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone. J Steroid Biochem Mol Biol. 2017 Nov;174:86-95. doi: 10.1016/j.jsbmb.2017.07.034. Epub 2017 Jul 31. PMID: 28774496.
2. Jonnalagadda B, Arockiasamy S, Krishnamoorthy S. Cellular growth factors as prospective therapeutic targets for combination therapy in androgen independent prostate cancer (AIPC). Life Sci. 2020 Oct 15;259:118208. doi: 10.1016/j.lfs.2020.118208. Epub 2020 Aug 4. PMID: 32763294.
3. Mostaghel EA, Zhang A, Hernandez S, Marck BT, Zhang X, Tamae D, Biehl HE, Tretiakova M, Bartlett J, Burns J, Dumpit R, Ang L, Matsumoto AM, Penning TM, Balk SP, Morrissey C, Corey E, True LD, Nelson PS. Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer. Clin Cancer Res. 2019 Jan 1;25(1):426-439. doi: 10.1158/1078-0432.CCR-18-1431. Epub 2018 Sep 4. PMID: 30181386; PMCID: PMC6320302
4. Pouliot F, Rouleau M, Neveu B, Toren P, Morin F, Vélot L, Ding K, Caron P, Lacombe L, Lévesque É, Klotz L, Guillemette C. Extragonadal Steroids Contribute Significantly to Androgen Receptor Activity and Development of Castration Resistance in Recurrent Prostate Cancer after Primary Therapy. J Urol. 2020 May;203(5):940-948. doi: 10.1097/JU.0000000000000699. Epub 2020 Dec 17. PMID: 31845837.
5. van Rooyen D, Yadav R, Scott EE, Swart AC. CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway. J Steroid Biochem Mol Biol. 2020 May;199:105614. doi: 10.1016/j.jsbmb.2020.105614. Epub 2020 Jan 30. PMID: 32007561.
6. Xiao L, Wang Y, Xu K, Hu H, Xu Z, Wu D, Wang Z, You W, Ng CF, Yu S, Chan FL. Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis. Cancer Res. 2018 May 1;78(9):2205-2218. doi: 10.1158/0008-5472.CAN-17-2341. Epub 2018 Feb 8. PMID: 29438990.