Identifying genetic vulnerabilities in neuroendocrine prostate cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

We will utilize CRISPR/CAS9 mediated gene inactivation to identify viability factors required for the growth of NEPC. We are screening PDX-derived organoid models using CRISPR/CAS9 libraries directed against transcription factors or epigenetic modulators. By screening in various metastatic prostate cancer classes, we are determining lineage-specific and genotype specific viability factors. Our main focus has been on RB1 deficient models, which express lineage plasticity encompassing adenocarcinoma, double negative and neuroendocrine phenotypes. We also have produced and characterized genetically-manipulated models to produce RB1 deficiencies in adenocarcinomas (LNCaP and LuCAP 167). We have identified transcription factors that selectively are required for viability in double negative prostate carrying RB1/TP53 loss genotypes. We are currently validating screen results with individual guide RNAs. Current work is directed at determining the role of PROX1 in lineage plasticity and commitment to the neuroendocrine lineage.