EMORY—A fast growing tumor eventually outpaces its blood and oxygen supply, which drives cancer cells to send out signals that attract new blood vessels. Now, researchers have identified a chemical that stops cells for responding to low oxygen.
Low oxygen, a condition known as hypoxia, actually helps a tumor survive, because radiation and chemotherapy are less effective under low-oxygen conditions.
Researchers at Emory University have identified a chemical that stops cells from making HIF1α (hypoxia-inducible factor 1-alpha), a key part of cells’ machinery for responding to hypoxia. The results were published in the Oct. 1 issue of Clinical Cancer Research.
The chemical, known as KC7F2, is toxic to several types of cancer cells. Under its influence, tumors essentially don’t know they are suffocating because they can’t make HIF1α. The chemical’s structure is related to that of psammaplin A, a compound isolated from marine sponges that also has antitumor properties.
HIF1α is part of a transcription factor that turns on other genes and is normally unstable and scarce, but low-oxygen conditions make it more stable. In low oxygen, it joins with a partner to encourage new blood vessel growth and reshape cells’ metabolism.
“The scientific community has been searching for small molecules that can specifically inhibit the function of HIF because it is essential for tumor growth under hypoxia,” says Erwin Van Meir, professor of neurosurgery and hematology and medical oncology at the Emory Winship Cancer Institute. “This is quite challenging as transcription factors are hard to target directly. A different approach is to prevent HIF synthesis, and KC7F2 acts in this fashion.”
Working with Van Meir, postdoctoral researchers Takuhito Narita and Shaoman Yin, in collaboration with K.C. Nicolaou’s group at the Scripps Research Institute in San Diego, sifted through thousands of chemicals to find one that counteracts HIF1α. More studies to determine exactly how KC7F2 prevents HIF1α synthesis and whether it will be effective in vivo are planned.
“The identification and development of novel HIF-1 pathway inhibitors may lead to the development of a new type of treatment for cancer,” the authors write, “potentially applicable to many solid malignancies.”
The research was supported by the National Institutes of Health, the American Brain Tumor Association, the Brain Tumor Foundation for Children, the Charlotte Geyer Foundation, and the Southeastern Brain Tumor Foundation.
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