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Development Project 4: Imaging HIF-1α/2α blockade in renal cell carcinoma bone metastasis, Kristy Weber, M.D.
Hypoxia and the hypoxia inducible factors (HIF-1 and -2) are associated with the transcriptional activation of a host of genes that increase invasion, metastasis, and resistance to treatment . Defects in the von Hippel-Lindau (VHL) gene are observed in 75% of sporadic clear-cell renal cell carcinoma (RCC), the major form of RCC . Loss of VHL function in RCC leads to constitutively activated HIF-1. Patients with RCC have tumors that are often refractory to treatment, and renal cell carcinoma bone metastasis (RBM) is a major cause of morbidity. RBM exhibits intense vascularity since VEGF and other proangiogenic molecules are highly overexpressed. Our hypothesis is that targeting of HIF-1α/2α will lead to decreased vascularity, reduced tumor growth, and reduction of bone destruction, in an orthotopic model of RBM. This hypothesis will be tested with the following two aims.
Aim 1. To characterize molecular changes following HIF-1α and HIF-2α downregulation in RBM cells in culture.
Aim 2. To inhibit HIF-1α and HIF-2α in an in vivo orthotopic model of RBM, and assess the effect on tumor vascularity, metabolism, and growth, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), MR spectroscopic imaging (MRSI), micro-CT, and immunohistochemical techniques.