Hormone signaling and translation control in advanced prostate cancer

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ABSTRACT The recent advent of highly potent inhibitors of the androgen receptor and androgen biosynthesis has had the unfortunate iatrogenic effect of fueling new lethal prostate cancer phenotypes in patients. In particular, non- neuroendocrine androgen receptor-low castration resistant prostate cancer (CRPC), an aggressive form of this disease, is increasing in occurrence amongst patients and is uniformly fatal. The main barriers against therapeutic advances are a paucity of relevant disease models and a very poor understanding of the mechanisms that give rise to this phenotype. The process of protein synthesis has long been considered subordinate to alterations at the levels of DNA and RNA in cancer etiology. However, work from our laboratory and others have revealed that protein synthesis control is a dynamic process that coordinates not only bulk mRNA translation, but also the specialized translation of distinct mRNAs important for cancer phenotypes. Recently, our laboratory has developed and characterized a new in vitro and in vivo toolkit of both human and murine androgen receptor-low CRPC. We have used these models to discover a critical link between androgen receptor signaling and the process of mRNA translation initiation, which is critical for androgen receptor-low CRPC growth. We hypothesize that androgen receptor-low CRPC is driven by the specific translation of distinct mRNA networks, thereby leading to persistent tumor growth, which may represent a therapeutic vulnerability. Our long-term objective is to utilize state-of-the-art mouse models, ribosome profiling, and patient derived xenografts to definitively investigate the fundamental link between the androgen receptor and protein synthesis control in a highly relevant and newly emerging disease course for prostate cancer patients. To do so, we will address the following aims: 1) determine the mechanism by which the androgen receptor communicates with the translation apparatus, 2) delineate how aberrant protein synthesis drives the translation of distinct oncogenic mRNAs, and 3) elucidate the therapeutic efficacy of targeting translation initiation in androgen receptor-low CRPC. Ultimately, these studies are poised to uncover a new paradigm for gene regulation in androgen receptor-low prostate cancer and provide the preclinical basis for targeting the protein synthesis apparatus in an increasingly common highly aggressive disease.