Development of Novel Nonagonist PPAR-Gamma Ligands for Lung Cancer Treatment
Technical Report,01 Aug 2015,31 Jul 2016
Massachusetts General Hospital Boston United States
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The overall goal of this grant is to establish the role of non-agonist PPAR-gamma ligands as potential therapeutic candidates for lung cancer. In this grant period, we have been able to identify a core gene set that is indicative of the inhibition of the phosphorylation of PPAR gamma in the setting of carboplatin treatment. Using gene set enrichment analysis, we have shown that p53 signaling and the DNA damage response is a key transcriptional target of inhibiting S273 phosphorylation. We have further shown genetically using lung cancer cell lines lacking p53, that p53 is an important mediator of ability of non-agonist PPAR-gamma ligands to sensitize lung cancer to DNA damaging agents. We have demonstrated a biochemical interaction between p53 and PPAR-gamma, which provides insight into the groups of patients for whom this combination therapy may benefit. We continue to make progress on the other aims of this grant, which aim to test this hypothesis in genetic animal models of lung cancer and to identify new partners for PPAR-gamma that may play a role in DNA repair.