Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma

Agonist ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma have been shown to induce terminal differentiation of normal preadipocytes and human liposarcoma cells in vitro. Because the differenti ation status of liposarcoma is predictive of clinical outcomes, modulation of the differentiation status of a tumor may favorably impact clinical beha vior. We have conducted a clinical trial for treatment of patients with adv anced liposarcoma by using the peroxisome proliferator-activated receptor-g amma ligand troglitazone, in which extensive correlative laboratory studies of tumor differentiation were performed. We report here the results of thr ee patients with intermediate to high-grade liposarcomas in whom troglitazo ne administration induced histologic and biochemical differentiation in viv o. Biopsies of tumors from each of these patients while on troglitazone dem onstrated histologic evidence of extensive lipid accumulation by tumor cell s and substantial increases in NMR-detectable tumor triglycerides compared with pretreatment biopsies. In addition, expression of several mRNA transcr ipts characteristic of differentiation in the adipocyte lineage was induced . There was also a marked reduction in immunohistochemical expression of Ki -67, a marker of cell proliferation. Together, these data indicate that ter minal adipocytic differentiation was induced in these malignant tumors by t roglitazone. These results indicate that lineage-appropriate differentiatio n can be induced pharmacologically in a human solid tumor.