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PI-103 Effective against Brain Cancer

argets to treat brain tumors.

In the Cell paper they described their success synthesizing a panel of different PI3 kinase inhibitors, showing for the first time the structural basis of the inhibitors' abilities to block different PI3 kinases. They used the new compounds to dissect the role of PI3 kinases in insulin signaling and in cancer. Drawing on this new tool, William Weiss, MD, associate professor of neurology at UCSF and an investigator in UCSF's Comprehensive Cancer Center, developed the strategy to treat gliomas. These cancers are the most common solid tumor of childhood, and about half of the people diagnosed with gliomas die within a year of diagnosis. Weiss and his colleagues report in the Cancer Cell paper that one PI3 kinase inhibitor in particular – PI-103 -- is unusually effective against gliomas in mice.

They believe the inhibitor is a promising drug candidate, and a UCSF neuro-oncologist is developing plans to launch a clinical trial within a year, Weiss says. The Weiss team discovered that the inhibitor's effectiveness lies in its dual impact. It inhibits both PI3 kinase and a protein kinase known as mTOR which acts downstream of PI3 kinase and is part of the cell's nutrient-sensing system. Clinical trials using inhibitors of mTOR alone have had disappointing results, Weiss says. One reason appears to be that the two kinases are part of a feedback loop. His group showed that mTOR inhibitors in clinical trials actually activate PI3-kinase while they inhibit mTOR. In effect, the drugs are blocking and encouraging cancer growth at the same time.

The new inhibitor offers a mechanism through which to block both the PI3 and the mTOR kinase pathways, a strategy that appears to be particularly effective at slowing growth of gliomas. Lead author on the Cancer Cell paper is Qi-Wen Fan, MD, PhD, assistant adjunct professor of neurology, in the Weiss lab. Co-authors along with Weiss, Shokat and Knight, all at UCSF, are David Gol
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