Adipokine Signaling as a Therapeutically Targetable Driver of Tumor Metabolism

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Project Summary: The link between obesity and cancer is well-established epidemiologically, but poorly understood at a mechanistic level. Clear cell renal cell carcinoma (ccRCC) is the most common form of renal cancer, and has clear ties with metabolic syndrome. ccRCC simultaneously demonstrates drastic metabolic rewiring at the histological and molecular levels that recently have been found to be essential for tumor development. Currently, however, the standard of care for ccRCC is targeted therapeutics against tyrosine kinases including the VEGF receptor, that in most cases lead to modest improvements in overall survival. Thus identification of new approaches to treat ccRCC is needed, and altered metabolism may offer a clinically useful foothold. We have investigated the characteristic lipid storage phenotype of ccRCC and identified a molecular mechanism that is driven in part by obesity. The present application focusses on a soluble adipokine produced by fat and tumors that suppresses lipid catabolism, and is essential for tumor growth. The very nature of a secreted factor leads to both diagnostic and therapeutic potential, and here we investigate the impact of inhibiting the adipokine, Chemerin, with multiple approaches including a monoclonal antibody in preclinical animal models of ccRCC, and a genetically engineered mouse model (GEMM). We will also dissect the mechanisms of action of Chemerin on tumor and non-tumor cells, and examine the significance of Chemerin isoforms in collected clinical specimens. Together, the aim of the proposal is to validate a novel target in ccRCC that could be combined with existing therapies to improve patient outcomes.