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  • Translational Research

    Targeting the PI3 Kinase Pathway

    jean-zhao-and-tom-roberts.jpgJean Zhao, PhD, and Thomas Roberts, PhD 

    Dana-Farber's interactive approach is exemplified by work on the PI3 kinase (PI3K) pathway, from the discovery of PI3K in the laboratory to clinical trials testing PI3K inhibitors in patients with cancer. Key nodes of the PI3 kinase intracellular signaling pathway are frequently mutated in cancer, particularly in solid tumors of the colon, breast, lung, and brain, as well as sarcomas. Since the 1980s when Thomas Roberts, PhD, co-chair of the Department of Cancer Biology, co-discovered PI3K, scientists have been hunting for a component of the kinase that could be targeted precisely - like Achilles' heel - to shut down unrestrained cell growth of PI3K-driven tumors.

    Roberts and Jean Zhao, PhD, also of the Department of Cancer Biology, subsequently found such a target: a catalytic subunit of PI3K, termed p110α, which is encoded by the PIK3CA gene. In their landmark study, Roberts and Zhao knocked out PIK3CA in mouse cells and discovered that the cells remained stubbornly resistant to oncogenic transformation, providing strong in vitro evidence that p110αa might represent a selective therapeutic target. They went on to show that formation of tumors arising from inactivation of the tumor suppressor PTEN was blocked by the knock-out of the PIK3CB gene encoding p110β, marking that protein as a potential drug target as well.

    Expanding on this work, Kwok-Kin Wong, MD, PhD, of Medical Oncology at Dana-Farber, and colleagues from Massachusetts General Hospital investigated the role of PIK3CA mutations in vivo. Wong genetically engineered mice to express in lung epithelia the p110&alhpa; activating mutation known as H1047R and then demonstrated that this mutation is indeed causal. When Wong then treated the mice with a PI3K inhibitor developed by Novartis, the tumors regressed dramatically. Independently, Zhao obtained similar data for breast tumors driven by the oncogenic PIK3CA in vivo.

    Dana-Farber now has four different PI3K-inhibiting drugs (two from Novartis, one each from Genentech and Exelixis) in clinical trials, with more on the way, says George Demetri, MD, whose laboratory colleagues in the Sarcoma Disease Center have demonstrated that PI3K pathway blockade is a promising therapeutic strategy for gastrointestinal stromal tumors that become resistant to matinib (Gleevec) and sunitinib (Sutent). "Dana-Farber is one of the few places in the world with this number of PI3K inhibitors in actual patient trials," remarks Demetri. "It reflects the commitment we've made to translational research, as well as the medical and scientific power we bring to collaborations with industry."

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