The AACR-Kure It Grants for Kidney Cancer Research represent a joint effort to promote and support innovative cancer research. These grants are available to independent investigators to develop and study new ideas and approaches that have direct application and relevance to kidney cancer patients. Applications are invited from researchers currently in their field as well as from investigators with experience in other areas of cancer research who have promising ideas or research approaches that can be applied to kidney cancer research. These grants support innovative translational research projects designed to improve the survival and quality of life of patients with kidney cancer and lead to individualized therapeutic options for treatment or the development of promising new cancer therapeutics for kidney cancer.
William Youngkwan Kim, M.D.
Assistant Professor of Medicine and Genetics, The University of North Carolina, Chapel Hill, NC
Defining the RCC kinome for target discovery and individualized therapy
"Approximately 65,000 new cases of renal cell carcinoma (RCC) occur annually in the US and its incidence is on the rise. While a number of kinase inhibitors are FDA approved for use in advanced RCC, their primary mode of action is believed to be antiangiogenic, via inhibition of the vascular endothelial growth factor receptor (VEGFR), or by inhibition of the mammalian target of rapamycin (mTOR). While sequencing of RCC has revealed inactivating mutations of tumor suppressor genes as well as genes involved in histone and chromatin modification, there is a paucity of kinase mutations. We have defined that there are three intrinsic kinomic subclasses of RCC and hypothesize that the RCC kinome, despite not being mutated, remains a tractable and actionable therapeutic target. Our work will define the activation state of the RCC kinome at the protein level and determine whether RCC kinomic subclass can predict therapeutic response to tailored kinase inhibition. The information garnered from this study should allow us to define a subset of kinases that are activated in RCC, differentiate kinomic subclasses of RCC, and lay the groundwork to begin to personalize kinase therapy based on the currently therapeutically actionable subset of the genome: the kinome."
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James W. Mier, M.D.
Associate Professor, Beth Israel Deaconess Medical Center, Boston, MA
HDM2/HDMX as a Therapeutic Target in Renal Cell Carcinoma
"Tyrosine kinase inhibitors (TKIs) that target VEGF receptor signaling are among the drugs most frequently used in the first-line treatment of patients with renal cell carcinoma (RCC). Although treatment with these agents delays disease progression for several months in the majority of patients, it almost never induces complete responses and in those patients that respond initially, resistance inevitably develops after a few months of treatment. My laboratory has been focused on the mechanisms by which RCCs escape from VEGF-targeted treatment. One of the adaptations we have observed in RCC xenografts that have become resistant to sunitinib is the disabling of p53 function. Although the p53 gene is intact in the majority of RCC and the expression of p53-dependent genes is readily induced by treatment, these alterations in gene expression are not sustained during TKI treatment, despite the persistence of p53 levels. The concurrent administration of an HDM2 antagonist, however, results in persistent expression of p21 and other p53-dependent genes and sustained tumor non-progression. Treatment with sunitinib results in an influx of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC), presumably due to the induction of the chemokine SDF-1. Both SDF-1 induction and the infiltration of tumor tissue by MDSC are suppressed by HDM2 antagonists. Finally, HDM2 antagonists suppress the expression of HIF-2a, the dominant oncoprotein in VHL-deficient RCC. Collectively, these data suggest that HDM2 antagonists might be ideal adjuncts to VEGF-targeted TKIs in the management of RCC. We hope to use the funds from Kure-It/AACR grant to further define the mechanisms by which HDM2 antagonists cooperate with TKIs to limit the growth and vascularity of RCC xenografts and ultimately, to apply our findings to the design of clinical trials that test the efficacy of these drug combinations in RCC patients."
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