Racial Difference in Prostate Cancer

Cedars-Sinai Medical Center, West Hollywood CA

Investigators

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Abstract

SUMMARY Men of West African ancestry (AA) in the United States have the highest risk of prostate cancer (PC) globally, and AA men frequently present with more aggressive disease. In the previous funding period, our goal was to identify master transcription factors (MTFs) that function more often in AA in comparison to EA PC. The competitive renewal project is based on our discovery of a novel interaction between Kaiso, an AA-associated TF, and ONECUT2 (OC2), a race-independent TF. Both of these MTFs are established malignancy drivers. Importantly, we have demonstrated that OC2 is directly targetable with a novel family of small molecule inhibitors (OC2i) that suppress established CRPC metastases in mice. We assembled a large dataset supporting a proposed genome-wide functional interaction between Kaiso and OC2. In this project we will investigate the role of this interaction in PC progression, and its potential therapeutic relevance, using in vitro models, quantitative analysis of human PC tissues, and pre-clinical studies of human patient-derived xenografts (PDXs) and PDX- derived organoids. Our results suggest that Kaiso and OC2 co-regulate a large gene expression network that promotes lineage plasticity and metastatic progression in PC cells, and that this network can potentially be suppressed by pharmacologic inhibition with OC2i. We will test two hypotheses in this project: 1) Kaiso cooperates with OC2 to promote lineage plasticity and drug resistance; and 2) Kaiso-active prostate tumors can be suppressed by pharmacologic inhibition of OC2. The Specific Aims are: Aim 1: Establish the role of the Kaiso-OC2 interaction in PC progression to lethal disease. In this aim we will elucidate the interdependence of the OC2 and Kaiso transcriptional programs, identify unique and inter-dependent OC2 and Kaiso chromatin partners and determine their functional roles, and determine the susceptibility of Kaiso activity to OC2 inhibition. Aim 2: Characterize the Kaiso-OC2 interaction and its effects on cell plasticity in AA and EA PC. Both OC2 and Kaiso traffic between the cytoplasm and nucleus. In this aim we will use multiplexed tissue staining, spatial transcriptomics and quantitative image analysis to assess whether OC2 and Kaiso expression and/or subcellular localization are biomarkers of PC lineage plasticity. Aim 3: Determine whether Kaiso-active tumors can be suppressed by OC2 inhibition. Because Kaiso activity correlates strongly with OC2 activity in diverse datasets, we will use human PDX models to determine whether Kaiso-active tumors can be suppressed by pharmacologic OC2 inhibition. Impact: These studies present a new avenue for deeper mechanistic understanding of PC lineage plasticity and scenarios of drug resistance in AA and EA men.