Targeting the UPR to Circumvent Endocrine Resistance in Breast Cancer
Technical Report,15 Sep 2014,14 Sep 2015
Georgetown University Washington United States
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In this Idea Expansion IDEX Grant, we propose that targeting IRE1 in endocrine resistant breast cancer cells with N-4-Phenoxy-phenyl-2-5-pyridin-3-yl-2H-1,2,4triazol-3-ylsulfanyl-acetamide NPPTA lead compound, or itsanalogs, will block pro-survival signaling from the UPR and prevent survival via pro-survival autophagy and aninhibition of apoptosis. We hypothesize that these effects will be mediated in part by the inhibition of XBP1 splicing and its ability to regulate BCL2 family members and NFB. Furthermore, a combination of NPPTA and AEs will interact synergistically to selectively kill AE resistant breast cancer cells in vitro and in vivo.