Understanding Resistance to Next Generation Antiandrogens

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PROJECT SUMMARY/ABSTRACT This R01 competitive renewal application focuses on a novel mechanism of acquired resistance to hormone therapy in castration resistant prostate cancer (CRPC) called lineage plasticity. During the initial 5 year funding cycle, we focused primarily on two other mechanisms of resistance: mutation or amplification of the androgen receptor (AR) and bypass of AR signaling through upregulation of the closely related glucocorticoid receptor. This work is described briefly in the Progress Report section of the Research Strategy and in the papers cited in the Progress Report Publication List. Here we shift our attention to a third mechanism of acquired resistance that we recently reported called lineage plasticity, in which prostate cancers escape hormone therapy by changing their identity from an AR dependent luminal lineage phenotype to an AR independent non-luminal lineage. This resistance mechanism occurs primarily in tumors deficient in the tumor suppressor genes TP53 and RB1 (which account for ~15% of CRPC) and is explained, in part, by upregulation of the reprogramming factor SOX2 which enables luminal epithelial cells to acquire characteristics of basal epithelial, mesenchymal and neuroendocrine cells that are no longer dependent on AR signaling for survival. We have developed genetically-defined mouse and human prostate cancer models (using organoid technology, xenografts and orthotopic tumor models) that recapitulate all the phenotypes of lineage plasticity observed in CRPC patients with reproducible, defined kinetics that make these models suitable for detailed mechanistic investigation. In Aim 1, we will identify the regulators of these lineage transitions, starting with a series of timecourse experiments using RNA-seq, ATAC-seq, chromatin ChIP-seq and single cell RNA-seq to define the transcriptomic and chromatin landscape changes associated with these changing phenotypes. Aim 2 will address the mechanism by which antiandrogen therapy can accelerate the development of lineage plasticity, which we postulate is through disruption of an AR-driven transcriptional program that helps maintain luminal identity. The results could have implications for the timing and context in which hormone therapy is used clinically. In Aim 3, we will identify candidate drug targets that block the development of lineage plasticity by conducting a pooled CRISPR screen of a library focused exclusively on chromatin modifying enzymes (selected based on our recent data implicating EZH2 as one such target). We will characterize the hits from this screen with the long range goal of developing combination therapy regimens (with antiandrogen therapy) that prevent resistance. In summary, this application will generate novel mechanistic insight into lineage plasticity in prostate cancer, with obvious implications for the clinical challenge of drug resistance. The findings are also likely to have relevance for other epithelial tumor types such as lung cancer, breast cancer and melanoma where evidence implicating lineage plasticity as a cause of drug resistance has also emerged.