Massachusetts General Hospital Boston United States
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 built on our gene expression data to show that a PPAR-gamma S273 phosphorylation signature is correlated with response to chemotherapy in lung cancer in publicly available datasets. 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 have also found new interactions of PPAR-gamma with other players in DNA damage repair, includingBRCA1 and gamma-H2AX. 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 novel partners for PPAR-gamma that may play a role in DNA repair.