Decisions on which grants to fund are a combination of the ratings of the proposal itself, an evaluation of the probability that the team will carry through, and the value of the results to the VHL Family Alliance community. While many of the applications submitted proposals which were “good science,” the Board and its advisors chose those that were felt to have the greatest potential in leading to better therapies for VHL.

Building a 3-D Model

We renewed our support for the project “Probing the molecular mechanisms of hypoxia inducible factor (HIF-1) dimerization and recognition by the von Hippel-Lindau tumor suppressor protein” by Georges Mer, Ph.D., of the Mayo Clinic. Dr. Mer is determining the 3-dimensional structure of the VHL complex and the energetics that hold it together. Pharmaceuticals can then use this model to design new small molecules or inhibitors to compensate for flaws in the structure, activating or deactivating proteins as needed.

HIF as a therapeutic target

We awarded a grant to Michael Zimmer, Ph.D., of Harvard Medical School and the Massachusetts General Hospital to study “HIF as a molecular therapeutic target.” Hypoxia-Inducible Factor (HIF) is one of the primary proteins targeted by VHL. His hypothesis is that if one could inhibit HIF function, one could stop the initiation or growth of tumors in

VHL. He will be examining two possible ways to interfere with HIF and and will assess the effects of this inhibition on tumor growth using mouse models.

Halting eye, brain, and spinal tumors

We have renewed our support for the second year of a study by Daniel George, M.D., of PTK-787 with VHL and hemangioblastoma. Dr. George was at Dana Farber Cancer Institute last year, and established the study in that location. This year he has moved to Duke University in Durham, North Carolina, and will be opening a second site there.

This is a drug which inhibits both VEGF and PDGF. VHL and its complex interacts with VEGF, PDGF, and HIF-1 alpha as well as other proteins, causing a variety of effects in different tissues. The fact that PTK-787 inhibits two of these it helpful. We may see in future that it will take multiple drugs together to fully constrain tumor growth.

Dr. George has recently completed a Phase II study of PTK787 with metastatic renal cell carcinoma (RCC), involving 42 patients which metastatic RCC who had failed all conventional therapy. Roughly 25% of all patients on the study demonstrated a 25% or greater decrease in tumor volumes, and significantly decreased blood flow to the tumors, effectively halting their progression.

This has led to the theory that the volume of blood flow to VHL hemangioblastomas of the brain and spinal cord may also be an indicator of the activity level of the tumor, and whether or not it may be poised to grow. The team is using functional MRI to measure blood flow, and measuring biologic effects of these tumors. Because of the variety of symptoms seen among people with VHL, it has been difficult to standardize ways of measuring the progress of tumors and of overall condition.

This study is still recruiting patients. The safety factors of this medication are pretty well known from studies of people with RCC and other cancers, and the side effects are very mild. What this study seeks to do is to show its effectiveness in halting or shrinking VHL tumors, especially eye, brain, and spinal tumors. The patient takes several pills a day, and comes for check-ups once a month for a year. If they can show at least two partial responses in the first 15 patients, the study will broaden to 47 patients.

Anyone who urgently needs surgery should have surgery. Anyone who has a tumor that is not immediately urgent but whose growth or surgical treatment would likely cause a deficit -- like a hemangioblastoma on the optic nerve -- should at least consider talking with Dr. George at Duke University in North Carolina (+1-919-668-8108) or his colleague Dr. Patrick Wen at Dana Farber Cancer Institute in Boston (+1-617-632 2166) and consider participating in this important study.

Because it is important to have consistent measurements of the tumors especially during these early stages of the trial, it is important to limit the number of machines and operators used. That means patient travel. Part of the grant is to assist patients with transportation for the trial, and Hospital Houses are available to assist with housing. Discuss these concerns also with the team.

As printed in the VHL Family Forum 11:4, Annual Report 2003. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org.