Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare but highly aggressive kidney cancers, with most patients dying within the first 5 years after diagnosis of metastatic disease in FH-deficient RCC, while less than 5% of patients with RMC survive longer than 36 months from diagnosis. Currently, there is no curative therapy for these two cancers. Both cancers occur in younger patients, with the mean age at diagnosis of 40 years for FH-deficient RCC and 28 years for RMC. Effective treatment strategies are desperately needed in these two highly lethal cancers. Bevacizumab plus erlotinib is a preferred first-line therapy for FH-deficient RC...

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Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare but highly aggressive kidney cancers, with most patients dying within the first 5 years after diagnosis of metastatic disease in FH-deficient RCC, while less than 5% of patients with RMC survive longer than 36 months from diagnosis. Currently, there is no curative therapy for these two cancers. Both cancers occur in younger patients, with the mean age at diagnosis of 40 years for FH-deficient RCC and 28 years for RMC. Effective treatment strategies are desperately needed in these two highly lethal cancers. Bevacizumab plus erlotinib is a preferred first-line therapy for FH-deficient RCC, whereas platinum-based chemotherapy consisting of either cisplatin or carboplatin plus paclitaxel is the preferred first-line therapy for RMC. Using patient resected tumor tissue, we developed mouse models of treatment-experienced RMC and FH-deficient RCC. We have observed tumor growth inhibition in our models when they are treated with erlotinib an epidermal growth factor (EGF) signaling inhibitor and observe increased tumor reduction when it is combined with a metabolic inhibitor. Our proposal will fully explore the connection between EGF signaling and metabolism in our RMC and FH-deficient RCC animal models and cell lines to determine the best synergistic combination of erlotinib and a metabolic inhibitor to induce tumor growth reduction and cell death. In addition, we will determine if radioactive glutamine and glucose positron emission tomography (PET) imaging can be a radiopharmaceutical biomarker for dual erlotinib and metabolic inhibition. The knowledge gained from the completion of this project and the creation of clinical trials based on it could have a significant impact on the overall survival of patients with RMC and FH-deficient RCC.

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