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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA172461-02
Application #
8601056
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$372,204
Indirect Cost
$146,078
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Yuzugullu, Haluk; Von, Thanh; Thorpe, Lauren M et al. (2016) NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell Discov 2:16030
Ni, Jing; Ramkissoon, Shakti H; Xie, Shaozhen et al. (2016) Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 22:723-6
Wang, Q; Liu, P; Spangle, J M et al. (2016) PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 35:3607-12
Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen et al. (2016) Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss. Elife 5:
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
Goel, Shom; Wang, Qi; Watt, April C et al. (2016) Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 29:255-69
Thorpe, Lauren M; Yuzugullu, Haluk; Zhao, Jean J (2015) PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 15:7-24
Matheny Jr, Ronald W; Riddle-Kottke, Melissa A; Leandry, Luis A et al. (2015) Role of phosphoinositide 3-OH kinase p110β in skeletal myogenesis. Mol Cell Biol 35:1182-96
Yuzugullu, Haluk; Baitsch, Lukas; Von, Thanh et al. (2015) A PI3K p110β-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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