Of the many proposals we received this year, the Research Advisory Board recommended and the Board of Directors approved funding of these three. We looked in particular for efforts that will bring new treatments to patients in the near term.

Most of us know about vaccinations that protect us from infectious diseases like polio and smallpox, but is it possible to be vaccinated against cancer? Or can we use cancer vaccines to treat existing disease? Vaccines work by introducing the infectious agent to the body to help the body develop its own defenses against the agent. Ironically, cancer deceives the immune system into thinking they are not dangerous, so that the body does not mount its full defenses.

Dr. Don Bellgrau of the University of Colorado in Denver, with his collaborators Richard Duke and Alex Franzusoff, has developed a method for tricking the immune system into seeing a dangerous situation worthy of its full defensive action. This full response then causes the body to destroy the tumor. With grant funding from VHLFA, Dr. Bellgrau will provide proof of the principle that individualized vaccines can be made for specific VHL mutation types, and develop a preclinical roadmap for the rapid use of this approach to treat renal cell carcinoma in humans.

Dr. George V. Thomas of University of California Los Angeles is focusing on the use of CCI-779 (also called temsirolimus, or “Torisel” by Wyeth), an inhibitor of mTOR tyrosine kinase, to stop kidney cancer tumors. While this drug shows promise in the lab, only about ten percent of the humans in the clinical trials saw significant slowing of tumor growth.

Dr. Thomas’ group recently demonstrated that human kidney cancer cells with loss of VHL dramatically respond to mTOR inhibitors, thereby providing a molecular explanation for the patient responses. Dr. Thomas will study the differences in response, correlate them with the VHL mutation type and other HIF-regulated genes in the patient’s genome, and learn how to predict in advance whether a patient is likely to respond to mTOR inhibitor therapy. He is also studying various other ways of measuring response, including PET scanning and markers in blood and urine

Dr. Susanne Schlisio of the Dana-Farber Cancer Research Institute in Boston, with funding from VHLFA, proposes to study the key to development of pheochromocytomas (“pheos”). Pheos arise from the same primitive cells that give rise to parts of the nervous system. These primitive cells are sometimes referred to as ‘neural crest’ cells. Some families are at high risk for developing Pheos (in the adrenals) or Paragangliomas (outside the adrenals) because they have alterations in specific genes (VHL, SDH, NF1). We recently discovered that these genes all play essential roles in determining whether neural crest cells live or die. In particular, when these genes are mutated, neural crest cells that should have died as part of the normal development of the fetus escape their death sentence and go on to cause tumor development later in life. We also showed that a gene called ‘EglN3’ (pronounced “eggelin3”) plays a critical role in this process. EglN3 promotes the death of neural crest cells whereas inhibiting EglN3 function has the opposite effect.

Dr. Schlisio and her colleagues have since learned that activating EglN3 kills pheo cells and other neural crest-derived tumors. In contrast EglN3 does not cause cell death in other types of cancer they have examined to date. In short, EglN3 appears to play a special role in the decision between life and death for neural crest tumors such as Pheos. They are trying to understand the mechanisms by which EglN3 causes cell death because this understanding might, in time, allow us to induce pheo cells to die in patients, which would shrink existing tumors or prevent new pheos.

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As printed in the VHL Family Forum 14:3, November 2006. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org