X-Message-Number: 27943
Date: Tue, 16 May 2006 20:08:55 -0700 (PDT)
From: Doug Skrecky <>
Subject: please forward to Thomas Donaldson

[Thomas may want to know about this: a UCSF neuro-oncologist is
developing plans to launch a clinical trial within a year, Weiss
says. For further information regarding contacts view the following link:


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

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 related kinases to identify which ones might be prime targets 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 Goldenberg, staff
research associate in neurology; Wei Yu, PhD, assistant research
anatomist; and David Stokoe, PhD, assistant professor in the Cancer
Research Institute.

Shokat, UCSF professor of cellular and molecular pharmacology, is also a
faculty affiliate in QB3, the Institute for Quantitative Biomedical

The research was supported by the Howard Hughes Medical Institute; the
Brain Tumor Society, the Goldhirsh Foundation, the Waxman Foundation, the
Sandler Family and the Brain Tumor SPORE Program at UCSF.

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