Understanding and Exploiting Loss of Y in Cancer - PROJECT SUMMARY My research as a physician-scientist has focused on the biology of bladder cancer (BC). I have translated this knowledge into diagnostic and prognostic markers and novel therapeutic targets with the goal of improving patient outcomes. My contributions include: identification of new growth and metastasis genes; description of BC heterogeneity using single cell and spatial transcriptomics that provided clinically relevant stratification; development of the “Molecular Twin”, an artificial intelligence (AI) platform that led to prognostic biomarkers superior to those in standard of care; discovery of Ral GTPase inhibitors, targeting a protein considered “undruggable”; and an in vivo functional genomic screen that discovered therapeutic targets enhancing effectiveness of immune checkpoint blockade (ICB). My most recent discovery was made while investigating why men have a higher incidence of BC than women, even though the latter experience more aggressive disease. We found that aggressive forms of BC in men lose the Y chromosome and that this Loss Of chromosome Y (LOY) drives BC growth while inducing T-cell exhaustion, which fortunately makes BC patients with LOY more sensitive to ICB. Interestingly, LOY in peripheral blood mononuclear cells (PBMCs) is the most common somatic genetic alteration in healthy men. This is associated with increased risk of BC and other epithelial tumor types. We found a high proportion of LOY in CD4 and CD8 T-cells in the microenvironment of human and murine BC tumors, and this independently correlated with poor outcomes. This was the first demonstration that concomitant presence of LOY in immune cells and LOY cancer cells in tumor samples adversely impacted prognosis. This led us to the hypothesis that urothelial and T-cell LOY conspire to promote carcinogenesis and tumor progression while inducing tumor vulnerabilities. With BC as a clinically relevant model to study LOY, we will use pioneering models and approaches we developed including novel genetically engineered mice (GEM) with tissue-specific and inducible LOY to evaluate the impact of LOY in urothelial and T-cells on carcinogenesis and progression. The impact of GEM-derived LOY T-cells and of human T-cells generated from unique differentiated LOY-induced pluripotent stem cells (iPSCs) on in vivo growth of Y+/LOY murine and human BC cells will be assessed, complementing GEM studies. Murine and human BC cell lines coupled with functional genomic and high throughput small molecule screens will identify novel therapeutic vulnerabilities of LOY cancer cells and LOY tumors. To validate results from models, we will evaluate LOY in PBMCs, tissue, and urine, in diverse BC patient cohorts to understand the impact of LOY on bladder carcinogenesis and patient outcomes and whether the impact is dependent on other patient characteristics such as race, ethnicity, and treatment. While a nascent field, the clinical relevance of LOY offers new and untapped opportunities to understand cancer. Our objective is to provide scientific insights into LOY biology that serve as foundations for prevention, early detection, and therapeutic approaches in bladder and other cancer types.
