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    • br Conclusion Growth survival and

    2023-10-09


    Conclusion Growth, survival, and invasion of most PCs have been shown to be androgen-dependent at the onset of castration therapy [31]. Thus, castration therapy has been central to systemic therapy and remains the standard approach to PC treatment. Even after progression to a castration-resistant state, residual androgens within PC tissue, which are metabolized from circulating adrenal androgens or synthesized de novo from cholesterol [8], [10], [11], [12], are thought to play a significant role in the growth and survival of PC tumors. Indeed, Montgomery et al. recently reported on the up-regulation of 17,20-lyase Pyrintegrin in androgen-refractory PC metastases, which supports the role of the intracrine steroidogenesis pathway in continued androgen synthesis, thereby maintaining androgens at levels in androgen-refractory PC that are able to maintain tumor survival [32]. In addition, our observation that DHEA treatment stimulates the growth of androgen-refractory PC xenografts in nude mice [9] further supports this idea. Therefore, treatments that inhibit the production of androgens from adrenal or tumor tissues could show efficacy in CRPC either alone or in combination with castration therapy. In conclusion, our findings show that orteronel, which inhibits 17,20-lyase activity with high enzyme-specificity, reversibly inhibits androgen synthesis in the testes and suppress the weight of androgen-dependent organs in rats while having minimal impact on steroid production in the adrenal glands. As the rat model of androgen synthesis shares common elements with that in humans, these results suggest that orteronel might be employed as an effective therapy for hormone-sensitive and CRPC. Orteronel is currently undergoing clinical evaluation in phase 2 in non-metastatic CRPC (NCT01046916) and in phase 3 in patients with metastatic CRPC who are chemotherapy-naïve (NCT01193244), those who have failed prior docetaxel therapy (NCT01193257), and in men with high risk prostate cancer (NCT01546987).
    Conflict of interest
    Acknowledgments All authors are employees of the Takeda Pharmaceutical Company Ltd., thus the work was supported in whole by Takeda. The authors would like to acknowledge Catherine Crookes and Mathew Southerden of FireKite for editing support, funded by Millennium Pharmaceuticals, Inc.
    Introduction The role of endogenous androgens in the development and progression of prostate cancer has long been recognized,1, 2 and patients with advanced prostate cancer have been efficiently treated with hormonal therapy such as surgical castration or the administration of a luteinizing-hormone-releasing-hormone (LH-RH) agonist. However, most of these patients eventually relapse during medical treatment and develop castration-resistant prostate cancer (CRPC). Sadly, management of later stages of this disease is often unsuccessful. The molecular mechanisms leading to the progression of CRPC are not yet fully defined, but recent studies3, 4, 5 have suggested that residual adrenal androgens that remain after castration could be responsible for CRPC evolution. Therefore, pharmacological methods to reduce adrenal androgen production can be considered as a new therapeutic option to delay CRPC progression. One possible approach to decrease androgens levels in tumor and plasma is to inhibit the 17,20-lyase activity of CYP17A1, which is an enzyme known to be responsible for androgen biosynthesis in both testes and adrenal glands. Indeed, over the past decade, steroidal and nonsteroidal inhibitors of 17,20-lyase6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 such as YM-116 and abiraterone acetate (Fig. 1) have been evaluated in clinical studies and have been found to effectively reduce circulating androgen levels. More recently we have also developed a novel series of 17,20-lyase inhibitors such as compound 1 (Fig. 1) which was observed to possess human 17,20-lyase inhibition with an IC50 of 16nM. However, our studies also found that 1 showed potent CYP3A4 inhibition with an IC50 value of 3600nM.