Raymond Pagliarini, PhD
Cambridge, Massachusetts, United States
The landscape of recurrent cancer “driver” mutations is rapidly becoming clear for a growing list of tumor types. However, many of these novel mutant genes encode proteins that are unprecedented as therapeutic targets. These include transcription factors, as well as regulators of epigenetic state and cellular metabolism. While these proteins constitute potential targets for therapeutics, our understanding of the basic biology around how they generate a cancer-dependent state is lacking. To gain a better understanding of such “unprecedented” genetic targets in cancer, we have focused our recent efforts on two examples: TMPRSS2:ERG and IDH.
- TMPRSS2:ERG translocations are present in roughly half of all prostate cancers, and generate ectopic expression of the ERG transcription factor. ERG induces a number of downstream effects, including altering the activity of the androgen receptor (AR), a key oncogenic driver in prostate cancer. We are characterizing the mechanism of how ERG alters gene expression, and whether any critical protein interaction partners are required for its oncogenic function.
- Highly recurrent point mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are present in a growing number of cancer types, notably glioma and AML. These mutations cause a gain-of-function enzymatic activity, the production of the metabolite 2-hydroxyglutarate (2-HG). 2-HG builds up to high concentrations in IDH mutant cells, and likely inhibits the function of a host of cellular enzymes that normally suppress tumor growth. We are using a variety of cellular models to elucidate the mechanism of how mutant IDH exerts its signaling function in cancer.
Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure.
Pagliarini R, Shao W, Sellers WR.
EMBO Rep. 2015 Mar;16(3):280-296.
TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation.
Mounir Z, Lin F, Lin VG, Korn JM, Yu Y, Valdez R, Aina OH, Buchwalter G, Jaffe AB, Korpal M, Zhu P, Brown M, Cardiff RD, Rocnik JL, Yang Y, Pagliarini R.
Oncogene. 2014 Sep 29. doi: 10.1038/onc.2014.308.
IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism.
Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR, Zhang X, Slocum KL, Pu M, Lin F, Vickers C, Joud-Caldwell C, Chung F, Yin H, Handly ED, Straub C, Growney JD, Vander Heiden MG, Murphy AN, Pagliarini R, Metallo CM.
Cancer Res. 2014 Jun 15;74(12):3317-31.
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