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

M Lizeth Orozco Morales; Catherine A Rinaldi; Emma de Jong; Sally M Lansley; Joel P A Gummer; Bence Olasz; Shabarinath Nambiar; Danika E Hope; Thomas H Casey; Y C Gary Lee; Connull Leslie; Gareth Nealon; David M Shackleford; Andrew K Powell; Marina Grimaldi; Patrick Balaguer; Rachael M Zemek; Anthony Bosco; Matthew J Piggott; Alice Vrielink; Richard A Lake; W Joost Lesterhuis

doi:10.1016/j.isci.2021.103571

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

iScience. 2021 Dec 4;25(1):103571. doi: 10.1016/j.isci.2021.103571. eCollection 2022 Jan 21.

Authors

M Lizeth Orozco Morales^{1

2}, Catherine A Rinaldi^{1

2

3}, Emma de Jong⁴, Sally M Lansley⁵, Joel P A Gummer^{6

7}, Bence Olasz⁸, Shabarinath Nambiar⁹, Danika E Hope^{1

2}, Thomas H Casey^{1

2}, Y C Gary Lee⁵, Connull Leslie¹⁰, Gareth Nealon⁸, David M Shackleford¹¹, Andrew K Powell¹¹, Marina Grimaldi¹², Patrick Balaguer¹², Rachael M Zemek⁴, Anthony Bosco⁴, Matthew J Piggott⁸, Alice Vrielink⁸, Richard A Lake^{1

2}, W Joost Lesterhuis^{1

2

4}

Affiliations

¹ School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia.
² National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia.
³ Centre for Microscopy Characterisation and Analysis, Nedlands, WA 6009, Australia.
⁴ Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia.
⁵ Institute for Respiratory Health, Nedlands, WA 6009, Australia.
⁶ School of Science, Department of Science, Edith Cowan University, Joondalup, WA 6027, Australia.
⁷ UWA Medical School, The University of Western Australia, Crawley, WA 6009, Australia.
⁸ School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia.
⁹ School of Veterinary and Life Science, Murdoch University, Murdoch, WA 6150, Australia.
¹⁰ Department of Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia.
¹¹ Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
¹² IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier 34090, France.

Abstract

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 tumors 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 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 anti-tumor effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma.

Keywords: Biological sciences; Metabolomics; Transcriptomics.