Combination of PPARg agonist pioglitazone and trabectedin induce adipocyte differentiation to overcome trabectedin resistance in myxoid liposarcomas

Purpose: This study was aimed at investigating whether the PPARg agonist pioglitazone - given in combination with trabectedin - is able to reactivate adipocytic differentiation in myxoid liposarcoma (MLS) patient-derived xenografts overcoming resistance to trabectedin. Experimental Design: The antitumor and biological effects of trabectedin, pioglitazone and the combination of the two drugs were investigated in nude mice bearing well-characterized MLS xenografts representative of innate or acquired resistance against trabectedin. Pioglitazone and trabectedin were given by daily oral and weekly i.v administrations, respectively. Molecular studies were performed by using microarrays approach, real-time PCR and Western blotting. Results: We found that the resistance of MLS against trabectedin is associated with the lack of activation of adipogenesis. PPARg agonist pioglitazone reactivated adipogenesis, assessed by histological and gene pathway analyses. Pioglitazone was well-tolerated and did not increase the toxicity of trabectedin. The ability of pioglitazone to reactivate adipocytic differentiation was observed by morphological examination, and it is consistent with the increased expression of genes such as ADIPOQ implicated in the adipogenesis process. The determination of adiponectin by Western blotting constitutes a good and reliable biomarker related to MLS adipocytic differentiation. Conclusions:The finding that the combination of pioglitazone and trabectedin induces terminal adipocytic differentiation of some MLSs with the complete pathological response and cure of tumor-bearing mice provides a strong rationale to test the combination of trabectedin and pioglitazone in patients with MLS.