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.
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