Polyoma middle T antigen has been a workhorse for the study of signaling pathways critical to cancer. MT is the oncogene of polyoma virus, but is itself devoid of biochemical activity. It transforms by stealing host cell components. More importantly, the virus has been quite judicious in its choices of host pathways to attack, and consequently the study of MT binding proteins has proved fruitful. Notably PI3 Kinase, perhaps the leading candidate for tumor therapy at this time, was actually introduced to the world via the work of the Cantley, Schaffhausen and Roberts labs on MT. Notably what we call PI3 Kinase is actually composed of a small family of closely related lipid kinases. My colleagues and I have continued our studies of MT and PI3K, and have recently used conditional knockouts of the key catalytic subunits of PI3K, p110? and p110?, to discover a previously unknown subtlety in the roles of these enzymes in signaling and cancer. Both the p110? and p110? isoforms appear to play distinct roles in oncogenic transformation, and, interestingly, isoform functionality varies according to tumor type. The roles of the 2 isoforms in insulin signaling are also quite distinct 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. In the next grant period we propose to exploit the known strengths of MT to study the roles of PI3K isoforms in much greater detail. We want to use the well known ability of MT to transform cells of multiple tissue types to study the isoform requirements for MT mediated transformation. This will allow us to decipher whether isoform dependence on tumor initiation is determined by the tissue type or the nature of the oncogenic lesion(s). We plan to examine the isoform dependence of MT tumors in the breast and prostate. We will also follow up on preliminary data, which suggests that isoform specific PI3K inhibitors might be used as chemopreventatives to ameliorate familial cancers arising from PI3K pathway activation. Finally we will examine mechanisms by which cells become resistant to PI3K inhibition.

Public Health Relevance

The first generation of PI3 Kinase inhibitors are just now entering clinical trials. The experiments proposed in this grant use murine tumor models driven by the viral oncogene MT antigen to (1) speed the use of second generation isoform specific PI3K inhibitors by determining how best to target individual PI3 Kinase isoforms in various tumor types, (2) investigate the potential of PI3K inhibitors as chemopreventatives and (3) determine how tumors may become resistant to PI3K inhibitors. Each of these aims has considerable potential to facilitate therapy for a number of important human tumor types.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030002-32
Application #
8408804
Study Section
Virology - A Study Section (VIRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1982-02-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
32
Fiscal Year
2013
Total Cost
$358,536
Indirect Cost
$132,983
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Pores Fernando, A T; Andrabi, S; Cizmecioglu, O et al. (2015) Polyoma small T antigen triggers cell death via mitotic catastrophe. Oncogene 34:2483-92
Utermark, Tamara; Schmit, Fabienne; Lee, Sang Hyun et al. (2014) The phosphatidylinositol 3-kinase (PI3K) isoform dependence of tumor formation is determined by the genetic mode of PI3K pathway activation rather than by tissue type. J Virol 88:10673-9
Schmit, Fabienne; Utermark, Tamara; Zhang, Sen et al. (2014) PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc Natl Acad Sci U S A 111:6395-400
Hwang, Justin H; Pores Fernando, Arun T; Faure, Nathalie et al. (2014) Polyomavirus small T antigen interacts with yes-associated protein to regulate cell survival and differentiation. J Virol 88:12055-64
Jia, Shidong; Gao, Xueliang; Lee, Sang Hyun et al. (2013) Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention. Cancer Discov 3:44-51
Ilic, Nina; Utermark, Tamara; Widlund, Hans R et al. (2011) PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. Proc Natl Acad Sci U S A 108:E699-708
Lee, Sang Hyun; Jia, Shidong; Zhu, Yanni et al. (2011) Transgenic expression of polyomavirus middle T antigen in the mouse prostate gives rise to carcinoma. J Virol 85:5581-92
Andrabi, Shaida; Hwang, Justin H; Choe, Jennifer Kean et al. (2011) Comparisons between murine polyomavirus and Simian virus 40 show significant differences in small T antigen function. J Virol 85:10649-58
Schaffhausen, Brian S; Roberts, Thomas M (2009) Lessons from polyoma middle T antigen on signaling and transformation: A DNA tumor virus contribution to the war on cancer. Virology 384:304-16
Jia, Shidong; Roberts, Thomas M; Zhao, Jean J (2009) Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol 21:199-208

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