This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 20-014. 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, castration resistant prostate cancer (CRPC) that is resistant to therapies such as enzalutamide and abiraterone are 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 uncovered a new functional link between androgen receptor signaling and the process of mRNA translation initiation. We found that decreases in androgen receptor activity lead to a compensatory increase in the activity of the eIF4F translation initiation complex which drives hormone signaling independence in CRPC. Importantly, this is mediated through the translation of distinct subsets of mRNAs. Based on these findings, we hypothesize that aberrant mRNA translation of distinct gene networks enables resistance to nuclear hormone receptor inhibition and CRPC progression. Our long-term objective is to utilize state-of-the-art patient derived models, ribosome profiling, and next-generation translation inhibitors 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 how alterations in mRNA translation initiation promote resistance to AR pathway directed therapies, and 2) delineate the translational gene networks that promote resistance to AR signaling inhibitors. Ultimately, these studies are poised to uncover a new paradigm for gene regulation in nuclear hormone receptor inhibitor resistance and provide the preclinical basis for targeting the protein synthesis apparatus in an increasingly common and highly aggressive disease.
We have uncovered a new mechanism of nuclear hormone receptor inhibitor-mediated drug resistance caused by aberrant translation initiation. The goal of this proposal is to understand the molecular underpinning of this resistance mechanism and develop a new therapeutic strategy to target this pernicious phenotype. If successful, this will lead to a new therapeutic option for patients with treatment resistant hormone addicted cancers.