Nine VHL research proposals were submitted to the VHLFA this year. Because of your generosity we were able to fund five of these. Nonetheless there is a great deal more work to be done. Hospitals and universities are cutting back their own spending on research, so those of us who want VHL research to move forward swiftly need to fill this gap. Even with a modest budget, however, we have made a significant contribution to the advancement of VHL research.

One of the stated goals of our research grants program is to assist young researchers in gathering sufficient data to prove the validity of their ideas so that they can qualify for other larger grants elsewhere and continue their research. In this regard, we are very happy to announce that in 2001 Dr. Maria Czyzyk-Krzeska, whom we funded for two years (1999-2001), was able to obtain substantial funding from the U.S. National Institutes of Health and the American Cancer Society for the continuation of her research on the Role of VHL in Pheochromocytoma. Dr. William Rigby (funded 2000-2002) has obtained funding from NIH to continue his research on VHL and proliferation of kidney cancer cells. Similarly, Dr. Ehud Gazit at Tel-Aviv University, whom we funded last year, has won a very large grant from the Israel Cancer Research Fund, to continue his work on ‘The Role of Protein Folding and Stability in the VHL Syndrome’. Dr. William Rigby, Tien Hsu, and William Kaelin presented papers in Padua. The list of papers published by our grantees has made an important contribution to the medical literature.

There are two aspects we are focusing on in this year’s grants. First, we continue to learn more about how the VHL protein (pVHL) operates in the cell – what it regulates in normal function, and what doesn’t work when pVHL is not present. Second, we are trying to move from this knowledge to real therapies. This work moves ahead more quickly when there is a "biological model", preferably one that goes through many generations in a short period of time so that genetic changes can be tracked. The mouse and even the fruit fly have a VHL gene. This shows how very essential a role the VHL gene plays in the cell.

We have renewed funding for a second year for Dr. Robert J. Duronio of the University of North Carolina to further his research on 'E3 Ubiquitin Ligase Complexes’. He is using a very powerful genetic system (the fruit fly) to study the function of pVHL as part of a group of proteins named "E3-ubiquitin ligase". pVHL’s role within the E3-ubiquitin ligase is often compared to that of a ‘garbage collector’, functioning as an "off" switch by gathering up certain cellular proteins that are needed for cellular growth and proliferation. The investigators have made good progress on the goals they set out to accomplish over the past year of funding, and are continuing and extending that work.

Dr. Georges Mer of the Mayo Clinic in Minnesota is investigating how the VHL protein binds to another

key protein named HIF1a. The association between HIF1a and pVHL has been shown by several research teams to be required for VHL to inhibit tumor growth. Dr. Mer is using Nuclear Magnetic Resonance Spectroscopy to determine the three-dimensional arrangement of pVHL and the fragment of HIF1alpha important for the binding between these two proteins. These studies will provide information about why certain mutations cause a loss of interaction and result in the formation of a tumor. In addition, this investigation will increase our knowledge of how pVHL and HIF1a interact, thus helping in the search for drug molecules that can restore the normal function of pVHL.

Dr. Tien Hsu of the Medical University of South Carolina is addressing how pVHL mutations cause cancer growth and metastasis. Although we know much about pVHL’s involvement in blood vessel formation, important questions pertaining to cancer onset and progression (as in RCC) remain unanswered. In the fruit fly, the author has identified a pVHL-interacting protein named nm23 (nm for non-metastatic). Mutations in the almost identical gene in humans have been correlated with many forms of metastatic tumors. He is investigating the functional relationship between this cancer-related gene and VHL disease. The implications of the study are three-fold:

It will shed light on the function of nm23, which is not fully understood at the present time.
It will provide evidence that pVHL can ‘activate’ the function of certain cellular proteins, and does not only function as a protein degradation factor.
It will point to nm23 as a target of therapeutic intervention. Fortunately, nm23 belongs to a class of enzymes that have been very well studied, so drug development should be feasible.

Dr. Daniel George of the Dana Farber Cancer Research Institute in Boston will use the Novartis Pharmaceuticals drug PTK787/ZK22584 (PTK/ZK) to carry out a Phase II clinical trial to treat patients with VHL, especially those with advanced central nervous system disease. PTK/ZK is an angiogenesis inhibitor that blocks the activity of two important proteins regulated by VHL: VEGF and PDGF, both of which stimulate new blood vessel growth. Early safety testing for this drug is being carried out with other kinds of cancers. The VHL study is due to open to VHL patients in December 2002.

In his proposal ‘Pheochromocytoma and Altered Mental Function,’ Pierre Jacomet hypothesizes that there is a direct relationship between pheochromocytomas and certain psychiatric conditions. Because there often is not a great deal of communication between a patient’s physicians and psychologists, the relationship may go undetected. Two out of three pheochromocytomas are discovered post-mortem. The objective is to compile data on the number of people suffering from panic attacks and other personality disorders that could be traced to undetected pheochromocytomas. With the help of statistical information, he hopes to raise the visibility of this issue so that health care professionals will be more likely to suspect and diagnose a pheochromocytoma, and possibly underlying VHL, MEN, and other pheo-related conditions. This project is being conducted in cooperation with the Catholic University Medical Center of Santiago, Chile, and Recalcine Pharmaceutical, South America.

As ever, we are very grateful to all our donors for making these grants possible. Together, we will continue to improve the management of VHL, and ultimately to find a cure.

Dr. Gorospe is Investigator Chief of the Cell Cycle Control Unit, Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health

Watch for more information about clinical trials on the website and in the March issue of the newsletter.

None of the trial drugs is ready yet for use as a preventive. Only people for whom the standard treatment is not an option are being considered for these early trials.

As printed in the VHL Family Forum 10:4, December 2002. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org.