Abstract
This study was aimed at investigating whether the PPARγ agonist pioglitazone-given in combination with trabectedin-is able to reactivate adipocytic differentiation in myxoid liposarcoma (MLS) patient-derived xenografts, overcoming resistance to trabectedin. 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. We found that the resistance of MLS against trabectedin is associated with the lack of activation of adipogenesis. The PPARγ agonist pioglitazone reactivated adipogenesis, assessed by histologic 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 morphologic 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. The finding that the combination of pioglitazone and trabectedin induces terminal adipocytic differentiation of some MLSs with the complete pathologic response and cure of tumor-bearing mice provides a strong rationale to test the combination of trabectedin and pioglitazone in patients with MLS.
Highlights
Trabectedin is a marine alkaloid originally extracted from a Caribbean tunicate and prepared synthetically
We found that the resistance of myxoid liposarcomas (MLS) against trabectedin is associated with the lack of activation of adipogenesis
The ability of pioglitazone to reactivate adipocytic differentiation was observed by morphologic examination, and it is consistent with the increased expression of genes such as ADIPOQ implicated in the adipogenesis process
Summary
Trabectedin is a marine alkaloid originally extracted from a Caribbean tunicate and prepared synthetically. It binds the minor groove of DNA, causing a distortion of the double helix that bends toward the major groove. Trabectedin interacts with DNA-repair pathways and directly affects trans-activated transcription. It modulates cytokine and chemokine production by cancer cells and tumor-associated macrophages. In 2015, trabectedin received FDA approval for the treatment of patients with unresectable or metastatic liposarcoma and leyomiosarcoma who received a prior anthracycline-containing regimen [5]. Within the different histologic subtypes of STS, leyomiosarcomas and liposarcomas seem to benefit more than other subtypes from treatment with trabectedin.
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