Targeting aggressive kidney cancer cells deficient in a metabolic enzyme
Abstracts
Initial Award Abstract |
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Cigarette smoking is one of the most recognized risk factors for the development and progression of kidney cancer (or renal cell carcinoma, RCC) and in one-third of newly diagnosed RCC cases the cancer has already spread to other organs. Metastatic spread of solid tumors makes kidney cancer incurable by surgical resection and consequently more difficult to treat. In recent years, cancer immunotherapy with so called checkpoint inhibitors, which improve the immune system's ability to kill cancer cells, have shown considerable potential in the treatment of RCC. However, many issues remain to be resolved, especially identification of patients who are unlikely to show early benefit from the therapy such that doctors can avoid treating patients with drugs that would cause side effects without much benefit. For these reasons, novel therapeutic approaches are urgently needed to improve the outcomes of RCC patients. We have discovered that the amount of a metabolic enzyme, methylthioadenosine phosphorylase (MTAP), is reduced in aggressive RCC cells, and similarly, that MTAP gene expression was downregulated after exposure to tobacco smoke. Experimentally removing MTAP expression in RCC cells increased their aggressiveness, including the amount of immune checkpoint proteins which enable cancer cells to better evade the immune system. We identified a cell signaling molecule, the type 1 insulin-like growth factor-1 receptor (IGF1R), as the top-one molecule regulated by MTAP expression. Given a decrease of MTAP in response to smoke exposure and in light of the importance of IGF1R in promoting tumor formation, we hypothesize that smoking-mediated MTAP loss and/or downregulation contributes to the activation of cellular signaling and RCC progression. The overall objective of this application is to determine the aggressive nature of smoke-associated RCC lacking MTAP. In this study, we will link smoking-related changes in metabolism (MTAP) and signal pathways to the regulation of the immune system’s ability to kill the cancer cells, thereby allowing stratification of patients into those who will or will not respond to specific novel therapies. Our study will likely provide a promising molecular model, potentially allowing for stratification of patients by smoking status and response to immunotherapies, and generate further hypotheses for developing new anticancer strategies. |
