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PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective

Orozco Morales, M.L., Rinaldi, C.A., de Jong, E., Lansley, S.M., Gummer, J.P.A., Olasz, B., Nambiar, S., Hope, D.E., Casey, T.H., Lee, Y.C.G., Leslie, C., Nealon, G., Shackleford, D.M., Powell, A.K., Grimaldi, M., Balaguer, P., Zemek, R.M., Bosco, A., Piggott, M.J., Vrielink, A., Lake, R.A. and Lesterhuis, W.J. (2021) PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective. iScience, 25 (1). Art. 103571.

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Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines 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 receptors PPARα 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 <i>in vitro</i>. 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 <i>in vitro</i> antitumour effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma.

Item Type: Journal Article
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Publisher: Elsevier
Copyright: © 2021 The Authors.
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