Dr. David Rickman is a molecular biologist and is an Associate Professor of Pathology and Laboratory Medicine. Dr. Rickman will, together with Dr. Himisha Beltran, Co-lead Project 2 on the WCM Prostate SPORE. The focus of Dr. Rickman’s lab is to elucidate the role of key oncogenic transcription factors in the biology of prostate cancer with an emphasis on the role of ETS family members and N-Myc in gene regulation (together with Drs. Beltran and Rubin, Cancer Discovery 2011), chromatin 3D architecture (together with Drs. Elemento and Rubin, PNAS 2012) and response to taxanes (together with Dr. Paraskevi Giannakakou, Nature Communications 2014). To this end, his lab has been developing in vitro and in vivo model systems that better mimic the context of the expression of these factors in vivo. For this project Dr. Rickman has also been overseeing the generation and characterization of all N-Myc pre-clinical models, optimization and development of assays highlighted in the research strategy including RNA-seq and chromatin immunoprecipitation (ChIP) in combination with next-generation DNA sequencing (ChIP-seq) for N-Myc and histone marks in prostate cancer cell lines and in human tissue samples. He has also performed next-generation RNA sequencing (RNA-Seq) to characterize global gene expression and Hi-C to characterize chromatin topology genome-wide in prostate cancer cells. Recently, his lab has shown that Aurora-A and N-Myc associate with and stabilize each other in neuroendocrine prostate cancer (NEPC) and generated mechanistic data showing that N-Myc over-expression is associated pro-metastatic, dedifferentiation and Polycomb Repressive Complex deregulated genes and AKT signaling (Dardenne E., Beltran, H … and Rickman DS, under review). The precise mechanism underlying these observations and whether co-targeting these pathways are more effective in N-Myc over-expressing tumors represents an unmet need and will be addressed in the proposal. In support of this project, his team has developed multiple pre-clinical models over-expressing N-Myc (isogenic cell lines, xenografts, transgenic mice and organoid cultures) of NEPC and transitioning CRPC to NEPC in order to determine the molecular features driving these cancer entities. He has established a fluorescent protein-protein assay (proximity ligation assay (PLA)) to detect N-Myc/Aurora-A complexes also optimized assays for the prostate cancer organoids to the investigation of N-Myc stability, N-Myc target gene expression and dose-response/cell viability for Aurora kinase A inhibitors (e.g. MLN8237). All of these pre-clinical models and resources are integral to ensure successful completion of the SPORE Project 2.