E-Poster Presentation 33rd Lorne Cancer Conference 2021

PPARα and PPARγ are associated with pleural mesothelioma growth, but therapeutic inhibition is ineffective in preclinical models   (#108)

Lizeth Orozco Morales 1 2 , Catherine A. Rinaldi 1 2 3 , Emma de Jong 4 , Sally M. Lansley 5 , Joel P.A. Gummer 6 , Bence Olasz 7 , Patrick Balaguer 8 , Matthew J. Piggott 7 , Alice Vrielink 7 , Richard A. Lake 1 2 , Joost Lesterhuis 1 2 4
  1. School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia
  2. National Centre for Asbestos Related Diseases, Nedlands, Western Australia, Australia
  3. Centre for Microscopy Characterisation and Analysis, Nedlands, Western Australia, Australia
  4. Telethon Kids Institute, West Perth, Western Australia, Australia
  5. Institute for Respiratory Health, Nedlands, Western Australia, Australia
  6. School of Science, Department of Science, Edith Cowan University, Joondalup, Western Australia, Australia
  7. School of Molecular Sciences, University of Western Australia, Crawley, Western Australia, Australia
  8. IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France

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, which dominates the clinical course of the disease. We compared mesothelioma cell lines that were injected either subcutaneously or intrapleurally in two murine models, and found that only the latter resulted in invasive and rapid growth. Using RNA sequencing and metabolomics analyses, we identified the nuclear receptors PPARα and PPARγ as key regulators of a transcriptional signature associated with invasive growth and we found increased abundance of endogenous PPAR ligands in pleural tumours. Binding assays and transcriptional reporter assays demonstrated that chemical probe GW6471 is a potent dual PPARα/γ antagonist. In vitro invasion and proliferation assays showed that GW6471 had anti-tumour efficacy. However, in mice, administration of GW6471 at doses providing sustained plasma concentrations above the IC50 values for both PPARs did not result in significant anti-mesothelioma efficacy. Hence, the in vitro anti-tumour effect of GW6471 is off-target, and dual PPARα/γ antagonism is not an effective treatment modality for mesothelioma.