RESEARCH

Our hope is that through research we will find ways of keeping tumors from forming, or at least keeping them small, and reduce the need for surgical intervention. With this end in mind, each year the VHL Family Alliance offers competitive grants to fund promising research that will lead to a cure for von Hippel-Lindau disease.

Research Grants Awarded in 2011

Disease-Causing Mutations

A grant was awarded for Eleanor Rattenberry, a second-year Ph.D. student in the laboratory of Dr. Eamonn R. Maher, University of Birmingham, England, to study the DNA changes that alter the function of the VHL protein and inhibit its ability to suppress cell growth. Not all VHL gene DNA changes will cause VHL disease and so if a patient in whom VHL disease is a possibility, but not certain, is found to have a DNA change that has not been detected previously, it is often unclear whether that person has VHL disease (in which case their relatives are at risk and they may develop further tumors) or if it is just a rare but benign DNA variant. In such circumstances it would be very helpful to have a test (or tests) available that would reliably establish whether the change is disease-causing or not. This project seeks to develop tests that will directly assess the functions of the VHL protein and enable predictions regarding whether the DNA change causes disease or not, and if it is a disease-causing mutation, which tumors are likely to develop. This will not only be of practical benefit for patients undergoing VHL gene testing but will also inform on the relationships between the function of the VHL protein and tumor development. Better understanding of this relationship will be helpful for developing new therapies for VHL disease.

Understanding Drug Resistance in Renal Cell Carcinoma

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.

With a total of over $1.3 million awarded to support research, previous grant recipients include

Donald Bellgrau, PhD University of Colorado, Denver	Othon Iliopoulis, MD Massachusetts General Hospital
Rupal Bhatt, MD, PhD Beth Israel Deaconess Medical Center	Shahriar Koochekpour, MD, PhD Louisiana State University Health Sciences Center
Robert D. Burk, MD Albert Einstein College of Medicine of Yeshiva University	Thera P. Links, MD, PhD University Medical Centre Groningen
Shufen Chen, MD, PhD University of North Carolina	Eamonn R. Maher, MD, FRCP University of Birmingham
Maria Czyzyk-Krzeska, MD, PhD Univeristy of Cincinnati	Georges Mer, PhD Mayo Clinic
Robert J. Duronio, PhD University of North Carolina, Chapel Hill	Armin Pause, PhD McGill University
Ian Frew, PhD University of Zurich	Brenda Petrella, PhD Dartmouth Medical School
Judith Frydman, PhD Stanford Universtiy	Kimryn Rathmell, MD, PhD University of North Carolina
Ehud Gazit, PhD Tel Aviv University	William Rigby, MD Dartmouth Medical School
Daniel J. George, MD Duke University Medical Center	Andreea Ruxandra-Schmitzer, PhD University of Montreal
Rachel Giles, PhD University Medical Center Utrecht	Susanne Schlisio, PhD Ludwig Institute for Cancer
James R. Gnarra, PhD University of Pittsburgh Medical Center	Bin Teh, MD, PhD Van Andel Institute
James Handa, MD Johns Hopkins University School of Medicine	George V. Thomas, MD Oregon Health and Science University’s Knight Cancer Institute
Tien Hsu, PhD Boston University Medical Center