New Molecule Inhibits Proliferation Of Broad Range Of Lethal Cancer Cells

Scientists have identified a new molecule that inhibits proliferation of a broad range of lethal malignant glioma cells in vitro and in vivo. The findings, published in the May issue of Cancer Cell, shed light on which PI3 kinase family members are most likely to play a role in cancer progression. This study reinforces the concept that successful small molecule kinase inhibitors must display a broad reactivity to effectively attenuate the complex signaling pathways involved in malignant transformation and to thwart to the ability of cancer cells to adapt to stress.

Lipid kinases belonging to the PI3 kinase family, made up of different isoforms, promote cell growth and survival. Aberrant regulation and activation of PI3 kinases has been implicated in several human malignancies. Although the specific mechanisms and PI3K-associated molecules involved in cancer are not clear, this kinase family represents a rational and promising target for design of new cancer therapeutics. Dr. William A. Weiss, from the Department of Neurology at the University of California, San Francisco and coworkers sought to identify which PI3 kinase isoforms are critical for growth and progression of malignant glioma cells. UCSF colleagues Zachary Knight and Kevan Shokat synthesized and characterized a series of novel inhibitors that span the different PI3 kinase isoforms (described in the May issue of Cell). Qi-Wen Fan in the Weiss lab screened these agents in glioma cell lines. One compound, PI-103, uniquely and potently blocked the growth of glioma cells.

The cellular activity of PI-103 was traced to its ability to cooperatively inhibit both the p110Ã¡ subunit of PI3 kinase and a downstream molecule called mTOR that also plays a critical role in cell growth. Although both of these molecules are members of the same signaling cascade, the researchers found that they must be concurrently inhibited because of a regulatory feedback loop that renders a monospecific inhibitor ineffective. Importantly, dual inhibition of p110Ã¡ and mTOR with a low dose of PI-103 elicited no drug-related toxicity and was highly effective against human gliomas transplanted into mice.

"These data suggest that combinatorial inhibition of mTOR and p110Ã¡ represents a safe and effective therapy in the treatment of cancers driven by aberrant signaling through PI3 kinase," says Dr. Weiss. "Glioma represents the most common primary brain tumor, and there are no curative medical therapies. Ultimately, we believe that PI-103 displays the hallmarks of the most successful cancer therapeutics that have been discovered to date as it exhibits a broad action without harmful side effects."

The researchers include Qi-Wen Fan, Zachary A. Knight, David D. Goldenberg, Wei Yu, Keith E. Mostov, David Stokoe, and William A. Weiss of the University of California, San Francisco in San Francisco, CA; Kevan M. Shokat of the Howard Hughes Medical Institute and the University of California, San Francisco in San Francisco, CA. This work was supported by the Brain Tumor Society, the Goldhirsh and Samuel G. Waxman Foundations, the Sandler Family, and the Brain Tumor SPORE Program.

Fan et al.: "A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma." Publishing in Cancer Cell 9, 341-349, May 2006. DOI 10.1016/j.ccr.2006.03.029 www.cancercell.org.

Here's another version of the article geared more toward the common folk.

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 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 Research.

The old saying about the devil in the details is probably very prescient here, as in many new cancer discoveries. A lot of the "discoveries" are in the news literally years after they are well known in the medical establishment. My wife who died of breast cancer, was taking meds that the media trumpeted earlier THIS year as a great step.....but she died in 2004 and fought for 3 years previous (Herceptin if you are curious, and yes it had short-term success). My layman's experience with modern cancer treatment has convinced me that current medicine and medical practice will not "cure" most of the things that are under investigation today. Science is looking under a lot of rocks, but I believe that simple factors that most Americans ignore can be the cause and the answer. Diet, environmental toxins (all kinds---even mold) and getting sleep are things that I ignore too, but.......
Keri's chemo was $4000 a week for the better part of 3 years, plus PET scans, MRI's, Xrays, and other standard meds. I'm still not a conspiracy nut on this.......but when the numbers are big, the stakes are higher and money is the root of all evil. http://www.kerispeakman.org/

Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.