Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

Among the critical problems today in prostate cancer therapy is the lack of an efficient and sustainable treatment for the most aggressive forms of prostate cancer (PCa). Along this clinical obstacle is the understanding that when treated, some of these aggressive forms of PCa develop resistance to therapy, and in other cases emerge with new characteristics that are untreatable. We recognize these hurdles as the most critical unmet need in the current management of prostate cancer.

This application offers an innovative first-in-class opportunity to address these clinical problems. Our proposal is based on work by a collaborative team of experts from three different institutes. The concerted work proposed here by Ze'ev Ronai, Ph.D. (Sanford-Burnham Medical Research Institute), Neil Bhowmick, Ph.D. (Cedars-Sinai Medical Center), and Martin Gleave, M.D. (Vancouver Prostate Center) offers a paradigm shift in prostate cancer therapy, as it focuses on a novel means to target castration-resistant prostate cancer (CRPC) and neuroendocrine (NE) forms of PCa, for which we lack effective therapies. The foundation for our proposed studies is summarized in two publications that were made in the top scientific journal Cancer Cell in 2010 and in 2013. Notably, a growing number of clinicians have been following our lead to develop new tools for monitoring and possible treatment of the most aggressive forms of PCa.

Our contribution to understanding how the most aggressive forms of PCa evolve, and hence how they could possibly be inhibited, has centered around a protein named Siah. Siah is a ubiquitin ligase, which means that it controls the stability (availability) of specific proteins in the cell. Like a brake pedal in an airplane, which determines not only the speed on ground but also the direction in the air, the ability to limit the availability of important proteins in the cell allows the determination of the fate of important regulatory processes. By analogy, to determine the speed and direction, Siah influences whether a cell will undergo death, survive, or morph into a new form (differentiate).

Our studies in PCa demonstrate that Siah controls the development of the neuroendocrine form of prostate cancer, among the most rare (3%-5%) and more aggressive forms of PCa, as well as a fraction (the more metastatic one) of the more prominent -- adenocarcinoma of the prostate. Over 30% of adenocarcinomas of the prostate are known to harbor neuroendocrine lesions (islands of cells that have signature of neuroendocrine cells); those are the tumors that are more prone to metastasize and that are associated with poorer prognosis. Siah is key for their development. Accordingly, we have shown that inhibition of Siah will prevent the development of neuroendocrine prostate tumors and will inhibit the metastasis of adenocarcinoma of the prostate, due to inhibition of neuroendocrine lesion formation.

Furthermore, in more recent studies we have shown that Siah is important player in the development CRPC. Mechanistically, Siah contributes to CRPC by controlling a fraction of androgen receptor (AR). As a result, a select pool of AR is constantly active, driving the CRPC program. Inhibition of Siah effectively diminished CRPC and sensitized it to treatment. As current therapies for CRPC reveal that some escape treatment by emerging as neuroendocrine forms of PCa, which are also regulated by Siah, we believe that evaluating the ability of Siah inhibitors in NE PCa, CRPC as well as adenocarcinoma of the prostate harboring neuroendocrine phenotype is timely and most important.

We have thus developed small molecule inhibitors for Siah that effectively inhibit PCa cell growth, and inhibit Siah activity. We propose to examine those we identified as well as improve on them further, for assessing the ability to develop Siah-based therapies against the most aggressive forms of PCa. We expect that our studies will pave the road for clinical evaluation of Siah inhibitors, alone and in combination with existing and developing therapies. We expect that within 2-4 years of completion of proposed studies, we should be positioned to perform pre-IND (investigational new drug) and subsequently clinical trials using Siah inhibitors.