Proteolytically Cleaved Receptors as Oncogenes and Therapeutic Targets

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DESCRIPTION (provided by applicant): My long term career objective is to be an independent investigator in an academic setting studying molecular signaling involved in epithelial tumorigenesis and their potential to be targeted for cancer therapy. The K99/R00 Pathway to Independence Award and the research proposed in this application will be instrumental in my professional development as a scientist and in transitioning to a Faculty Position. ENVIRONMENT. During the mentored K99 phase of the award I will perform the proposed research under the direct guidance of Dr. Witte at the University of California at Los Angeles (UCLA). Dr. Witte is a world- renowned leader in the field of cancer research. Dr. Witte will further my training in cancer biology since his laboratory has developed a unique set of approaches to study prostate cell biology and cancer pathogenesis. I have also assembled an advisory board with a co-mentor and several consultants/collaborators including: Dr. Kurdistani, Professor in the Department of Biological Chemistry at UCLA, is an expert in functional genomics; Dr. Huang, Professor of Pathology and Laboratory Medicine and Director of Urologic Pathology at UCLA, is an expert in prostate clinical-pathology; Dr. Pienta, Professor of Oncology and Pharmacology and Molecular Sciences at Johns Hopkins University, is a leader in the developing of new therapeutic programs for prostate cancer; Dr. Rubin, Professor of Pathology and Laboratory Medicine and Oncology at Weill Cornell Medical College, is an internationally recognized pathologist and a leader in prostate cancer genomics. Dr. Horvath, Professor of Biostatistics and Human Genetics and Head of the Array Data Analysis Group at UCLA, is a leader in developing bioinformatics methods. During the K99 phase of the Award, I will gain training in the areas of functional genomics, and strategies to translate molecular signaling into therapeutics. This training will be a stepping stone for my independent career as a cancer biologist. RESEARCH. I have previously characterized the oncogenic role of the type I transmembrane protein Trop2 in prostate tumorigenesis. My previous studies demonstrated that Trop2 is activated through regulated intramembrane proteolysis resulting in cleavage of Trop2 at two distinct sites. Upon cleavage, the intracellular domain of Trop2 translocates into the nucleus and initiates a downstream signaling cascade driving cellular proliferation and tumor initiation. My recent studies identified Notch1, another type I transmembrane protein regulated through proteolytic cleavages, as a key player in prostate tumorigenesis. My preliminary results point to an existing cross-talk between Trop2 and Notch1 receptors. In Aim 1, I will investigate the functional cooperation between Trop2 and Notch1 receptors in prostate tumor initiation and progression in vivo utilizing the recently established primary human tissue recombination assay. In Aim 2, I will define new downstream targets of Trop2 and identify the biochemical relationship between Trop2 and Notch1 signaling. In Aim 3, I will test combined inhibition of Trop2 and Notch1 signaling as a new therapeutic strategy in cancer.