PPARα and PPARγ activation is associated with pleural mesothelioma invasion, but therapeutic inhibition is ineffective in preclinical models

Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, resulting in pain and shortness of breath. We compared mesothelioma cell lines that were injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Pleural tumours displayed a transcriptional signature consistent with increased activity of nuclear receptorsPPARα and PPARγ and with an increased abundance of endogenous PPAR-activating ligands. We found that chemical probe GW6471 is a potent dual PPARα/γ antagonist with anti-invasive and anti-proliferative activity in vitro. However, administration of GW6471 at doses that provided sustained plasma exposure levels sufficient for inhibition of PPARα/γ transcriptional activity did not result in significant anti-mesothelioma activity in mice. Lastly, we demonstrate that the in vitro antitumour effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma. Examination of invasive and non invasive mesothelioma in murine model