Brain Tumors & HIF-1

Attacking Brain Tumors Through HIF-1

The glioblastoma multiforme (GBM) is the most common and most aggressive of the primary brain tumors. This deadly form of brain cancer has a two-year survival rate of just 27 percent. The median survival time is 1.2 years. These aren't the kind of odds anyone wants to hear when facing a serious illness. The American Cancer Society forecasts more than 20,000 new cases of primary brain tumors annually, about 5,000 of which will be GBM.

Erwin G. Van Meir, PhD
Erwin Van Meir

A new set of molecular compounds have shown promise in reducing the growth of human brain tumors in animal models, however, and may hold potential as a treatment for GBM and other cancers, says researcher Erwin G. Van Meir, PhD, Co-Director of the Winship Cancer Institute's Brain Tumor Program at Emory University. "This new candidate drug may prove a valuable addition to the scarce arsenal of anti- tumor therapies available today," Van Meir says. The secret lies in attacking the tumors cells when they are stressed by the lack of available oxygen, a condition known as hypoxia.

"Rapidly expanding tumors soon outgrow the capacity of existing blood vessels to deliver oxygen," he explains. "To survive hypoxia, tumor cells modify their metabolism and induce growth of new blood vessels in the tumor. A central molecule that is responsible for these adaptive processes is Hypoxia Inducible Factor-1 (HIF-1). Therefore, inactivating HIF-1 is expected to cause hypoxic tumor cells to die."

Van Meir's lab has developed a new class of natural product-like drugs that efficiently inhibit the activity of HIF-1 in tumor cells. To find these compounds, ten thousand small chemical molecules were screened through collaborative research between Van Meir and K.C. Nicolaou, Chairman of the Chemistry Department at the Scripps Research Institute in La Jolla, California.

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The most promising proved to be a small molecule compound with the code name KCN1, which has demonstrated anti-tumor effects with minimal toxicity in animal models. "After a ten-week treatment, the average tumor volume in the KCN1-treated mice was more than five-fold lower than in the control group," Van Meir says.

Van Meir's research has led to the discovery of several potential therapeutics for the treatment of cancer, including the small molecule HIF-1 inhibitors and a viral based therapy, says Justin Burns, licensing associate at Emory's Office of Technology Transfer. "He has been able to rapidly move from a basic understanding of the cellular machinery actions to develop interventions,” Burns says. “We think his work has tremendous promise."

A native of Belgium, Van Meir has extensive experience in cancer research. He was trained in molecular biology at the universities of Fribourg and Lausanne, Switzerland, and did postdoctoral work at the Ludwig Institute for Cancer Research in San Diego. He joined the Emory faculty in 1998.

Effective treatment for GBM tumors is particularly challenging. GBM tumors rapidly infiltrate surrounding tissue, so surgery alone is seldom curative. Surgery followed by radiation and chemotherapy has achieved better results, but five-year survival rates remain below 20 percent even in these patients.

Van Meir says the new drugs would likely best work in synergy with currently existing therapy.

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