Research Projects Your Dollars are Supporting

• Understanding Drug Resistance in Renal Cell Carcinoma

• Disease-Causing Mutations

A grant was awarded for Dr. Haifeng Yang of the Cleveland Clinic to study Drug Resistance in clear cell renal cell carcinoma (ccRCC). Mutations of the VHL tumor suppressor gene cause von Hippel-Lindau disease as well as sporadic ccRCC, the most common kidney cancer in the general population.

Historically ccRCC has been resistant to all forms of traditional chemotherapy. VEGFR inhibitors generated positive clinical outcomes but not cures, so more drugs against new targets are needed. Sup­pression of a potent oncogene EGFR signifi­cantly blocked kidney tumor growth in mouse models, but EGFR inhibitors failed in kidney cancer patients.

Recently it was found that a histone-modifying enzyme JARID1C was mutated in ccRCC. They found that when there is no VHL protein in the cell, JARID1C was responsible for the global reduction of an important epigenetic marker and suppression of some HIF-responsive genes. While HIF2a is an oncogene in ccRCC, promoting tumor growth, JARID1C is a tumor suppressor. When JARID1C was knocked down in ccRCC cells in a mouse model, the tumor grew significantly. HIF-dependent JARID1C activation also led to innate drug resistance to EGFR inhibitors in VHL-deficient kidney cancer cells.

Dr. Yang will investigate further the role of JARID1C and explore ways to defeat resistance so EGFR inhibitors could become useful drugs to VHL patients.

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As printed in the VHL Family Forum 19:4, November 2011. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.