The PI3 Kinase pathway is a leading candidate for targeted tumor therapy at this time. This pathway is frequently activated via mutation in both commonly occurring and rare tumor types. Current PI3K directed therapies are targeted to the catalytic subunits of the so-called Class I enzymes. Of the four Class I isoforms, only p110beta and p110beta are expressed in all tissues. Both the p110beta and p110beta isoforms appear to play distinct roles in oncogenic transformation, and, interestingly, isoform functionality varies according to tumor type. Only p110beta is activated by mutations in human tumors. Experiments with conditional knockout mice and shRNAs in human tumor cell lines have shown that p110beta is the key isoform for signaling from oncogenic receptor tyrosine kinases as well as oncogenes such as ras or polyoma middle T antigen. Surprisingly p110beta has been shown to be key for tumors featuring Pten loss, though mechanistic understanding of this data has been lacking. The roles of the two isoforms in insulin signaling are also quite distinct, with p110beta carrying the larger part of the signal, suggesting that inhibiting individual isoforms could have fewer side-effects than the pan inhibitors now entering the clinic. Thus we are excited that the differences in the roles of the isoforms may be exploited to make safer second-generation drugs for PI3Ks. While pharma has concentrated on p110beta specific inhibitors, we have worked to develop a tool compound, Kin-193, that can be used to treat Pten null tumors in mice via inhibition of p110beta. In this grant we seek to understand the mechanism(s) by which p110beta is specifically activated in Pten null tumors, to characterize Kin-193's effects on human xenograft tumors in mice, and to determine how resistance to p110beta inhibitors may arise.
Cancer is frequent cause of death and morbidity. Many cancers arise at least in part due to the loss of expression of the tumor suppressor gene known as Pten. This grant requests funds to study a new type of treatment for tumors arising from Pten loss. Successful completion of the work in this grant may help to cure a large cohort of human tumors.
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|Wang, Yubao; Begley, Michael; Li, Qing et al. (2016) Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival. Proc Natl Acad Sci U S A 113:9810-5|
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|Yuzugullu, Haluk; Baitsch, Lukas; Von, Thanh et al. (2015) A PI3K p110Î²-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis. Nat Commun 6:8501|
|Wang, Yubao; Zhang, Tinghu; Kwiatkowski, Nicholas et al. (2015) CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell 163:174-86|
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