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 VT464. 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.

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

“…64 In particular, abiraterone acetate has recently been approved in the United States for the treatment of hormone-dependent and castration-resistant prostate cancer patients. 65 In addition, the inhibition of CYP17 by ketoconazole also exhibited tumor-suppressive effects in ovarian cancer.…”

CYP17A1 Maintains the Survival of Glioblastomas by Regulating SAR1-Mediated Endoplasmic Reticulum Health and Redox Homeostasis

“…Previously, we showed that CYP17A1 upregulation confers drug resistance to glioblastomas by increasing DHEA synthesis [7,8]. Hence, we aimed to study whether abiraterone, a well-known CYP17A1 inhibitor [12], potentially suppresses glioblastomas. As shown in Figure 1A, abiraterone significantly inhibited the survival of T98G, A172, and patient-derived PT#3 glioblastoma cells.…”

“…Thus, we are not sure whether SAR1 is a novel substrate of CYP17A1, even though we found an interaction of CYP17A1 with SAR1. Through 17α-hydroxylase and 17,20 lyase activities, multiple steps of steroidogenesis require CYP17A1, including the production of 17α-hydroxy-pregnenolone and DHEA [12,16]. In contrast, whether the enzymatic activity of CYP17A1 is involved in protein interactions, or whether it participates in other cellular processes, remains largely unclear.…”

“…Therefore, we cannot say definitively that abiraterone-induced ER stress and ROS accumulation are caused by CYP17A1 inhibition, based on our evidence. To improve the selectivity of inhibitory targeting of CYP17A1, orteronel (TAK-700), galaterone (TOK-001), and seviteronel (VT-464) were developed to treat diseases caused by the overproduction of androgens [12]. To specifically understand the role of CYP17A1 in glioblastomas, the effects of these inhibitors on glioblastomas need to be further elucidated.…”

Role of the androgen signaling axis in genitourinary malignancies

“…Additionally, the molecules VT-464 and galeterone are both pharmaceutical agents used to specifically target the 17,20-lyase reaction over 17α-hydroxylase activity. In contrast to abiraterone and orteronel, these newly described agents have an increased specificity towards 17,20-lyase, which results in the inhibition of testosterone synthesis while causing only minimal changes to patient cortisol levels (16).…”