New compound unusually potent at blocking brain cancer growth

By determining how a class of compounds blocks signaling in cells, UCSF scientists have identified what is perhaps the most potent drug candidate yet against a highly lethal kind of brain tumor.

The compound, known as PI-103, shows unique potency against cancer cell proliferation in studies of mice with grafts of human glioma cells. Gliomas are the most common form of brain cancer, and have proven very difficult to treat.

The unique effectiveness of PI-103 stems from its ability to attack two separate steps in the series of signals that trigger the spread of cancer. The dual blockade proved to be a safe and effective inhibitor of cancer cell proliferation in mice with the human tumors, the scientists found.

The glioma research is being published online May 15 by the journal Cancer Cell. A description of the strategy used to identify the molecular level action of the inhibitors was published online by the journal Cell on April 27.

Food and Drug Administration approval five years ago of the cancer drug Gleevec marked a promising new strategy against cancer. Gleevec was the first drug on the market designed to block ubiquitous signaling molecules called protein kinases enzymes known to trigger normal cell proliferation, and in the case of cancer, the growth of tumors. Another group of kinases, called lipid kinases are now emerging as important new targets, especially PI3 alpha kinase, an enzyme often found to be overactive in brain, breast, colon and stomach cancers.

But the sheer number of related kinases 15 in the PI3 kinase family alone and uncertainty about how each acts in the body has stalled progress. Broad spectrum drugs that inhibit many related kinases inevitably cause toxicity and are poor drug candidates.

To overcome this hurdle, Kevan Shokat, PhD, a Howard Hughes Medical Institute investigator at UCSF, and Zachary Knight, a postdoctoral fellow in his lab, developed a strategy to systematically inhibit many different but r

Contact: Wallace Ravven
University of California - San Francisco

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