Kidney Cancer Researcher Wins DoD Grant
Geoffrey Clark, Associate Professor of molecular biology at the University of Louisville, KY, was selected to receive a 3-year grant, commencing in July 2009, as part of the Department of Defense’s Peer Reviewed Medical Research Program (PRMRP). Dr. Clark’s research will focus on a tumor suppressor gene called RASSF1A, which, along with the VHL gene, is turned off in a majority of kidney cancers with clear cell pathology. In one aspect of his study, Dr. Clark will research drugs that turn on RASSF1A to observe their effect on kidney cancer progression.
The fact that kidney cancer is currently one of the 19 diseases that are eligible for research grants from PRMRP is a direct result of the lobbying campaigns that Action to Cure Kidney Cancer (ACKC) has conducted for the last 4 years in Washington, DC. Dr. Clark’s grant is projected to be in the range of $485,000.
ACKC will add a non-technical summary of Dr. Clark’s project on our website, http://www.ackc.org/. In the meantime, we have posted the technical abstract below.
We want to congratulate all the advocates who joined with us in our past lobbying campaigns to get DoD research money for kidney cancer. Dr. Clark is the second researcher to obtain a grant from the Department of Defense’s PRMRP. Two years ago, Dr. Maria Czyzyk-Kreska of the University of Cincinnati won a $933,000 award to do genetic research in kidney cancer. Including kidney cancer as one of the diseases eligible for PRMRP grants is a direct result of the lobbying campaigns initiated by ACKC. Our ultimate goal, however, is to have Congress authorize $15 million a year targeted only for kidney cancer research as part of DoD’s Congressionally Directed Medical Research Program. Currently five diseases receive funds from this program with breast cancer receiving $150 million and prostate cancer getting $80 million a year.
Scientists have long known that loss of the VHL gene is a causative factor for the clear cell variety of kidney cancer (encompassing 75-80% of all renal cancers). However, disabling the VHL gene in mice does not cause kidney cancer, only renal cysts. This observation implies that some other factor must be involved to cause the cancer. In fact, in observation of clear cell cases, researchers have noted the loss of RASSF1A, which, like VHL, is a tumor suppressor gene. In addition, RASSF1A and VHL form a protein complex so may have associated functions, one or more of which might involve the suppression of kidney cancer. Dr. Clark’s hypothesis is that knocking out only VHL in mice doesn’t cause kidney cancer, and knocking out only RASSF1A doesn’t cause kidney cancer, but deactivating both VHL and RASSF1A does cause kidney cancer, which will replicate the situation that is present in humans. Therefore, if it is possible to develop a mouse with both tumor suppressor genes inactivated, and that mouse subsequently develops kidney cancer, scientists then have an excellent model for developing treatments for clear cell type renal carcinoma.
The RASSF1A gene is turned off by a process called methylation, which doesn’t actually modify or mutate the gene itself but simply turns it off. There are agents that can reverse the process, i.e. demethylate the gene. One of Dr. Clark’s objectives, once he has developed the mouse model, will be to treat the mouse with a demethylating agent designed to turn RASF1A back on and see if that will make the renal tumor more susceptible to standard therapy. This process is called epigenetic therapy, defined as the process whereby the gene’s DNA is itself not modified, but the expression of the gene is altered.
Following is the Public Abstract of the award.
Over 12,000 patients are expected to die of Advanced Renal Cell Carcinoma (RCC) in the USA each year. The disease exhibits high levels of relapse and tumors are frequently resistant to chemotherapy or radiation. Thus, there is a great need for improved understanding and treatment options for this disease.
The best known genetic determinant of RCC is the Von Hippel-Lindau (VHL) tumor suppressor. Defects in VHL function are detected in 70% of sporadic RCC and contribute to a familial form of RCC. However, mice with VHL knocked out in the kidney do not develop RCC. This suggests that some other genetic lesion, in addition to VHL, must occur. It has now been found that a second tumor suppressor, RASSF1A, is inactivated in almost all RCC. Loss of RASSF1A function makes cells resistant to apoptotic stimuli and so may contribute to the notorious resistance of RCC to conventional chemo and radiation therapy. Moreover, we have now shown that RASSF1A and VHL can form a tumor suppressor complex in kidney cells. Thus we hypothesize that inactivation of RASSF1A in addition to inactivation of VHL is critical to the development of RCC.
Our first objective is to test this hypothesis with a series of in vitro experiments and to generate a novel transgenic mouse where RASSF1A and VHL function are both disrupted in the kidney. We predict that when present in a RASSF1A null background, the kidney specific VHL knockout will progress to the kidney tumors that it cannot do on its own. This will generate the first effective model for VHL driven RCC in animals which could greatly facilitate the development of novel therapies in humans.
Our second objective is to test the hypothesis that the frequent loss of RASSF1A function in RCC may provide an opportunity for novel targeted therapies. Epigenetic therapy may restore the function of the dormant RASSF1A gene, reactivating apoptotic pathways and hence re-sensitizing the RCC cells to conventional therapy. New and improved microtubule destabilizing chemotherapeutics may also be particularly effective in RASSF1A defective RCC because loss of RASSF1A expression sensitizes cells to such agents.
The ultimate applicability of the work will provide a novel animal model for VHL driven RCC as a more physiologically relevant model for novel drug testing. It may also identify novel therapeutic approaches that are likely to be effective in the treatment of RCC and particularly patients with VHL driven RCC. The clinical benefits would include over-coming chemo and radiation resistance to tumors as well as the development of more effective and less toxic therapies. There are some risks associated with the use of epigenetic therapy as it may result in the activation of genes that are supposed to be repressed in the normal cell. However, the epigenetic therapy would be transient and the potential gain in clinical outcome balances the risk.
One of the novel agents under consideration in this proposal, Indibulin, is already in Phase I testing. Thus, if our results are positive then further clinical trials directed against RCC could be established fairly rapidly. Moreover, demonstrating a vital connection between the two most important tumor suppressors yet identified in RCC would open up a whole new area of research in RCC to determine the mechanism of action of the tumor suppressor complex.