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Targeting Prolyl Peptidases in Triple-Negative Breast Cancer
Technical Report,01 Feb 2016,31 Jan 2017
Rush University of Medical Center Chicago United States
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Triple negative breast cancer TNBC is an aggressive sub-type with limited treatment options and poor prognosis. The most life-threatening aspects of TNBC are therapy resistance and metastasis. To improve survival in TNBC patients it will be necessary block metastasis and decrease tumor cell survival. We identified a protein called PRCP prolylcarboxypeptidase that promotes metastasis and survival in breast cancer cells. We found high expression of PRCP in TNBC patients coincides with decreased recurrence-free survival worse outcome. In a drug screen we identified a potent inhibitor of PRCP and its related family member prolyl endopeptidase PREP and showed that it has anti-tumor activity in vivo. The goals of this grant are 1 to determine the molecular mechanism by which PRCP and PREP promotes survival and metastasis and, 2 to test our drug candidate for its ability to reduce TNBC tumor growth and target metastatic TNBC tumors. These goals are pursued in two specific aims. Results obtained so far show that PRCPPREP inhibition reduces IRS1 and IRS2 protein levels, blocks proliferation, and induces death in multiple TNBC cell lines of different sub-types. These effects appear to result, at least in part, through IRS12, AKT, and mTORC1 inhibition. Results also indicate the PRCPPREP inhibitor we identified can inhibit growth of human TNBC tumors in mice, supporting PRCPPREP as treatment targets and our inhibitor as a therapeutic agent.
APPROVED FOR PUBLIC RELEASE