Researchers you are supporting 2007-2008

-- James T. Gnarra, Ph.D., Research Advisor

In the 15 years since finding of the VHL gene, research on the VHL gene and the protein it encodes has brought together scientists and physicians from many diverse areas.  Genetic testing for VHL has become a straightforward laboratory test that not only helps diagnose VHL, but is becoming increasingly important in the clinic. Where once only a handful of laboratories were familiar with VHL, now scores of laboratories are involved in VHL research.  We now know that the VHL protein is central to a number of important processes in the cell. 

Among other things, the VHL protein controls the activity of hypoxia-inducible factor (HIF), a “master regulator” of cell activities, especially of angiogenesis, or the growth of new blood vessels that will feed any of a number of tumors, or form an angioma.

VHL is also important in the structural integrity of the cell, and in controlling the process.  We now understand that all clear cell kidney cancer tumors in the general population have an abnormality in the VHL gene in the tumor.

Two years ago, there were no drugs to help at all with VHL, nor with kidney cancer.  This year there are four approved drugs for advanced kidney cancer, but still none “for VHL.”  There are also many new drugs working their way toward FDA approval for one or more types of cancer.  Most of these are based in whole or in part on research on the VHL gene.

The Cancer Research Fund of the VHL Family Alliance was able to fund 3 proposals of the 13 very high quality proposals that were submitted this year.  The research that will be performed by these groups will address important clinical, translational, and basic research questions that are very relevant to our understanding of VHL and how VHL patients will be treated in the future. 

Thera P. Links, M.D., Ph.D., of the University of Groningen in the Netherlands, is pursuing a project of “Visualizing VEGF producing lesions in Von Hippel-Lindau.”

The first thing that happens in the development of a VHL lesion is that the second copy of the VHL gene is inactivated in a cell.  Without the VHL protein, there is heightened production of vascular endothelial growth factor (VEGF).  The greater the production of VEGF, the higher the growth rate of the tumor. 

Until recently, it was not possible to measure the VEGF levels inside the tumor without removing the tumor.  Dr. Links and colleagues have developed a radioactive labeled antibody, based on bevacizumab (Avastin) which binds to VEGF, making it possible to visualize and quantify VEGF in tumors of colorectal and melanoma patients using a PET scan.

This project will use PET scans on 30 people with VHL to detect and quantify the level of VEGF production in VHL-associated lesions.  The goal is to use this information to formulate a plan of monitoring and treatment with surgery and/or drug therapy to manage the health of these patients.

Rupal Bhatt, M.D., Ph.D., of Beth Israel Deaconess Hospital and the Dana Farber/Harvard Cancer Center in Boston, will study the “Role of the Interferon Gamma Pathway in Resistance to Antiangiogenic Therapy.”

People with VHL are sometimes being offered treatment with one of a class of drugs known as tyrosine kinase inhibitors (TKI’s).  Eventually the tumors become resistant to treatment, and begin to grow again.  Even though the drug is blocking the VEGF pathwaythe tumor seems to find a “detour” and begin to grow again.  Bhatt’s team believe they have identified the “detour” being used.  The project will confirm this hypothesis in mice, test it in VHL patients, and try to find a way to block this path so that these and newer TKI’s can be used effectively for longer periods of time.

James Handa, M.D., of the Wilmer Eye Institute of Johns Hopkins Medical Institute in Baltimore, will study the “Use of a novel genetic animal model to study the molecular pathogenesis of retinal hemangioblastomas in VHL disease.”

Retinal hemangioblastomas are the most common manifestation of VHL, occurring in the vast majority of VHL patients, often as the first sign of the disease.

It is essential to identify lesions early and control them.  However, there are only limited treatment options available, which are not always successful.  Better treatment options are needed. Dr. Handa and his colleagues have recently developed an animal model that reproduces the retinal hemangioblastomas observed in patients with VHL disease. This novel genetic model represents the first animal model for VHL retinal hemangioblastomas. In this research proposal they will use this animal model to identify new methods for the early diagnosis and treatment of VHL-associated retinal  hemangioblastomas.