Exploitation of a New Targetable Node in the AR Signaling Pathway in Prostate Cancer
Abstract
Patients with recurrent or metastatic prostate cancer typically undergo androgen-deprivation therapies designed to (a) block androgen production and/or (b) inhibit androgen receptor (AR) activity. These treatments are not curative, and resistance to therapy is common and most often fatal. It was initially thought that, once resistance to any endocrine therapy develops, targeting of the AR axis was no longer a viable therapeutic option. Unexpectedly, however, recent studies have shown that AR remains a key regulator of tumor growth and survival in castration-resistant prostate cancer (CRPC). This continued dependence on AR signaling in CRPC provided the rationale for the development of second-generation antiandrogens like enzalutamide and AR-directed PROTACS, as well as androgen synthesis inhibitors, like abiraterone. However, the therapeutic lifespan of these contemporary medicines is relatively short, and there is a growing sentiment in the field that the resolution of the resistance problem does not lie in the development of better AR antagonists/androgen synthesis inhibitors per se but in the development of effective treatment strategies to inhibit AR action/growth promoting pathways in a unique manner in advanced disease or delay the onset of resistance to current hormonal therapies. We have contributed to these efforts by developing a new discovery platform for PCa therapeutics and using it to screen for drugs that either work alone or which enhance the efficacy of targeting AR in growth conditions that mimic the environment of the tumor. Interestingly, in these conditions, while existing anti-androgens effectively inhibit classical AR responsive genes (i.e., PSA), they are considerably less effective at inhibiting the androgen-regulated processes that are required for cell proliferation. From our drug screens emerged a series of structurally and mechanistically distinct regulators of the retinoic X receptor (RXR), a member of the nuclear receptor superfamily of ligand-regulated transcription factors that has largely been ignored as a therapeutic target in PCa. The drugs we identified exhibit activities that distinguish them from classical RXR modulators and reflecting this pharmacological property are classified as selective retinoic acid related-receptor modulators (SRXRMs). These drugs work by binding to their primary target, RXR, and by inducing a specific conformational change in this receptor, modulate two downstream signaling pathways in a manner that is unfavorable to cancer cell growth. Importantly, we have shown in two different animal models of CRPC that exemplars of this new class of drugs effectively inhibit tumor growth by restoring sensitivity to AR antagonists. Our mechanistic studies revealed that targeting this axis inhibited several growth promoting pathways that were not targeted by AR antagonists and that they reduced c-MYC expression, an oncogene whose role in driving prostate cancer aggressiveness is well established. Leveraging these findings, we propose that appropriate targeting of the RXR axis would both restore sensitivity to antiandrogens/inhibitors of androgen biosynthesis and prolong their therapeutic lifespan. In studies outlined in Aim 1, we will explore the molecular mechanism(s) by which SRXRMs impact PCa pathobiology and define the extent to which the expression of the targets of these drugs track with clinicopathological features in patients with prostate cancer. In Aim 2, we propose to use structure-based drug discovery and guided medicinal chemistry design methods to generate clinically useful analogs of our lead compounds. Such mechanism-guided drug discovery approaches are an established strength of our research group. The studies in Aim 3 will employ validated models of PCa tumor growth and metastasis to evaluate the likely therapeutic utility of the SRXRMs we have developed, and will continue to develop, during the course of these studies. The overall goal
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210698
Entities
People
- Donald P McDonnell
Organizations
- Duke University
- United States Army