The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature

Abstract

Given prostate cancer is driven, in part, by its responsiveness to androgens, treatments historically employ methods for their removal from circulation. Approaches as crude as castration, and more recently blockade of androgen synthesis or receptor binding, are still of limited use long term, since other steroids of adrenal origin or tumor origin can supersede that role as the 'castration resistant' tumor re-emerges. Broader inhibition of steroidogenesis using relatively nonselective P450 inhibitors such as ketoconazole is not an alternative since a general disruption of steroid biosynthesis is neither safe nor effective. The recent emergence of drugs more selectively targeting CYP17 have been more effective, and yet extension of life has been on the scale of months rather than years. It is now becoming clear this shortcoming arises from the adaptive capabilities of many tumors to initiate local steroid synthesis and/or become responsive to novel early pathway adrenal steroids that are synthesized when lyase activity is not selectively blocked, and ACTH rises in the face of declining cortisol feedback. Abiraterone has been described as a lyase selective inhibitor, yet its use still requires co-administration of prednisone to suppress such a rise of ACTH and fall in cortisol. So is creation of a selective lyase inhibitor even possible? Can C19 steroid production be achieved without a prominent decline in cortisol and corresponding rise in ACTH? Decades of scientific study of CYP17 in humans and nonhuman primates, as well as nature's own experiments of gene mutations in humans, reveal 'true' or 'isolated' 17,20 lyase deficiency does quite selectively prevent C19 steroid biosynthesis whereas simple 17 hydroxylase deficiency also suppresses cortisol. We propose these known outcomes of natural mutations should be used to guide analysis of clinical trials and long term outcomes of CYP17 targeted drugs. In this review, we use that framework to re-evaluate the basic and clinical outcomes of many compounds being used or in development for treatment of castration resistant prostate cancer. Specifically, we include the nonselective drug ketoconazole, and then the CYP17 targeted drugs abiraterone, orteronel (TAK-700), galaterone (TOK-001), and seviteronel (VT-464). Using this framework, we can fully discriminate the clinical outcomes for ketoconazole, a drug with broad specificity, yet clinically ineffective, from that of abiraterone, the first CYP17 targeted therapy that is limited by its need for prednisone co-therapy. We also can identify potential next generation CYP17 targeted drugs now emerging that show signs of being far more 17,20 lyase selective. We conclude that a future for improved therapy without substantial cortisol decline, thus avoiding prednisone co-administration, seems possible at long last.

Keywords: CYP17A1; Cancer; Hydroxylase; Inhibitor; Lyase; Prostate.

Figure 1. ACTH-dependent, specialized steroidogenic pathways of the adrenal cortex

In the zona glomerulosa (ZR, green shading), an absence of CYP17A1 leads to aldosterone as the major hormone released, while in the zona fasciculata (ZF, grey shading), expression of CYP17A1 without CytB5 leads to predominant 17-hydroxylase activity and cortisol as the major hormone released. In the zona reticularis (ZR, orange-pink shading), expression of CYP17A1 together with CytB5 now enhances 17,20 lyase activity. Coexpression of sulfotransferase, but diminished expression of 3beta-hydroxysteroid dehydrogenase, within the ZR leads to DHEA and DHEAS as the major products released post adrenarche, and androstenedione as a minor product (dashed arrow). Under physiological conditions, ACTH stimulated ZF and ZR steroidogenic function is regulated by cortisol negative feedback alone, while angiotensin II (and circulating K+) predominantly regulate ZG steroidogenic function.

Figure 2. An alternative “backdoor” steroidogenic pathway to androgen production can operate in parallel to the “classical” steroidogenic pathway

The “backdoor” pathway utilizes pregnenolone and progesterone to synthesize dihydrotestosterone, a highly potent androgen, without progressing through “classical” pathways of production to DHEA and androstenedione. Co-expression of CYP17A1 and CytB5, however, are required for both pathways to operate. Modified from 33.

Figure 3. Altered steroid hormone production in the adrenal cortex induced following diminished CYP17A1 expression or selective 17-hydroxylase inhibition

In the case of selective 17 hydroxylase inhibition, 17,20 lyase function is also correspondingly lost (red Xs).. While androgen biosynthesis is now prevented, cortisol is also lost (grey text). This releases negative feedback control of circulating ACTH, and the ensuing excess ACTH levels over-stimulate production and release of both aldosterone and early steroid pathway products into the circulation (red arrows). Other details are provided in the legend to Figure 1.

Figure 4. Altered steroid hormone production in both “classical” and “backdoor” pathways following diminished expression of CYP17A1 or selective 17-hydroxylase inhibition (red Xs)

While androgen biosynthesis is absent, cortisol is also absent (grey text), releasing negative feedback control on ACTH, and resulting in excessive ACTH drive also over-stimulating “backdoor” products of 5alpha-DHP and allopregnanolone, in addition to supraphysiologic over-stimulation of the adrenal ZG aldosterone pathway (red arrows; see also Figure 3).

Figure 5. Altered steroid hormone production in both “classical” and “backdoor” pathways following selectively diminished lyase activity within CYP17A1 (red Xs)

While androgen biosynthesis through both “classical” and “backdoor” pathways is now absent (grey text), sufficient cortisol biosynthesis remains to maintain negative feedback control on ACTH, thus avoiding the abnormal steroid hormone excesses of hydroxylase deficiency or blockade shown in Figures 3 and 4.