Mechanisms of Bladder Cancer Development and Its Therapeutic Vulnerabilities to Preventive and Interventive Therapy.

Overall Summary This P01 program project is focused on bladder cancer, a common human malignancy with significant morbidity and mortality in the United States and across the world. The goal is to develop new and more effective therapies for both early and advanced disease. This goal will be accomplished with molecular characterization of mucosal field effects and their evolution to aggressive and therapy-resistant bladder cancer. Whole-organ mapping studies will be complemented by molecular characterization of two mechanisms based on downregulation of lysophosphatidic acid receptor 6 (LPAR6) and calcium-binding protein 39-like (CAB39L). These studies will be supplemented by in-depth investigations of the role of luminal and basal phenotypic switch in the urothelium and its role in therapeutic responses of bladder cancer cells. This P01 project has three well-defined goals: 1) development of molecular profiles of bladder cancer evolution from field effects to clinically aggressive disease on a whole-organ scale and investigating LPAR6 and CAB39L role, which contribute to bladder carcinogenesis by dysregulating the urothelial differentiation program; 2) characterization of the role of luminal differentiation program and its role in tumor formation; and 3) characterization of the role of luminal to basal plasticity in response to interferon therapy. These goals will be accomplished in three projects. Project 1: Understanding the Evolution of Bladder Cancer from Field Effects; Project 2: The Role of Nuclear Receptors Signaling in Bladder Cancer; and Project 3: Identifying Molecular Vulnerabilities to Improve Interferon Gene Therapy in Bladder Cancer. These projects will be supported by the Administrative, Pathology and Biostatistics and Bioinformatics Cores. Collaborative studies by Projects 1 and 2 as well as by Projects 1 and 3 will focus on the role of luminal to basal plasticity and dysregulated urothelial differentiation in therapeutic responses of bladder cancer. Projects 1 and 2 will focus on the role of luminal dysregulation controlled by nuclear receptors such as Pparg in the evolution of bladder cancer from mucosal field effects. Projects 1 and 3 will investigate the expression pattern of IFN target genes in the evolution of bladder cancer from mucosal field effects as well as the role of luminal to basal plasticity in therapeutic response. The work is proposed by a multi-institutional team of scientists who have worked on bladder cancer for decades and have documented collaborations focused on bladder cancer. The studies proposed in this P01 program project are highly promising options for early detection, prevention, and treatment of bladder cancer.