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

Harvard University, Cambridge, Massachusetts, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/1999; 96(7):3951-6. DOI: 10.1073/pnas.96.7.3951
Source: PubMed


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 differentiation status of liposarcoma is predictive of clinical outcomes, modulation of the differentiation status of a tumor may favorably impact clinical behavior. We have conducted a clinical trial for treatment of patients with advanced liposarcoma by using the peroxisome proliferator-activated receptor-gamma ligand troglitazone, in which extensive correlative laboratory studies of tumor differentiation were performed. We report here the results of three patients with intermediate to high-grade liposarcomas in whom troglitazone administration induced histologic and biochemical differentiation in vivo. Biopsies of tumors from each of these patients while on troglitazone demonstrated histologic evidence of extensive lipid accumulation by tumor cells and substantial increases in NMR-detectable tumor triglycerides compared with pretreatment biopsies. In addition, expression of several mRNA transcripts 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 terminal adipocytic differentiation was induced in these malignant tumors by troglitazone. These results indicate that lineage-appropriate differentiation can be induced pharmacologically in a human solid tumor.

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Available from: Elisabetta Mueller, Sep 29, 2015
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    • "Although not frequently observed, synaptophysin expression [25] has been recently confirmed by gene expression profiling analysis [23]. Finally, PPR-gamma, firstly described to be involved in ECM signaling pathway [23], is also expressed in many other cancers including myxoid liposarcomas [26-28], and therefore it can hardly be diagnostically helpful. From these findings it appears that cytogenetic-molecular analysis substantially helps in distinguishing EMC from other tumor entities. "
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    ABSTRACT: Extraskeletal myxoid chondrosarcoma (EMC) is a rare subgroup within soft tissue sarcomas. Its sensitivity to chemotherapy is reported to be low. We retrospectively reviewed a series of 11 EMC patients treated as from 2001 at a single institution and/or within the Italian Rare Cancer Network (RCN) with anthracycline-based chemotherapy. Pathologic diagnosis was centrally reviewed in all cases and confirmed by the presence of the specific chromosomal rearrangements, involving the NR4A3 gene locus on chromosome 9. Eleven patients treated with anthracycline-based chemotherapy were included (M/F: 9/2 - mean age: 52 years - translocated/evaluated for translocation: 11/16 - site of primary: lower limb/other = 9/2 - metastatic = 11 - front line/ further line = 10/1 - anthracycline as single agent/ combined with ifosfamide = 1/10). Ten patients are evaluable for response. Overall, best response according to RECIST was: partial response (PR) = 4 (40 %), stable disease (SD) = 3, progressive disease (PD) = 3 cases. Median PFS was 8 (range 2-10) months. By contrast to what reported so far, anthracycline-based chemotherapy is active in a distinct proportion of EMC patients.
    12/2013; 3(1):16. DOI:10.1186/2045-3329-3-16
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    • "Despite a plausible biologic basis, reported human studies using PPAR-gamma agonists for liposarcoma have thus far had mixed results with low numbers of enrolled patients. Demetri et al. reported a proof-of-mechanism study conducted at the Dana Farber Cancer Institute in three liposarcoma patients (2 MRC, 1 pleomorphic), using the anti-diabetic thiazolidinedione drug, troglitazone [59]. Tumor biopsies and mass-spectroscopy imaging demonstrated histologic and biochemical differentiation with accumulation of lipid droplets. "
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    ABSTRACT: Liposarcoma is one of the most common adult soft tissue sarcomas and consists of three histologic subtypes (well and dedifferentiated, myxoid/round cell, and pleomorphic). Surgery is the mainstay of treatment for localized disease; however for unresectable or metastatic disease, effective treatment options are currently limited. In the past decade, a better understanding of the distinct genetic and molecular aberrations for each of the three histologic subtypes has led to the development of several novel systemic therapies. Data from phase I and early phase II clinical trials have been reported. Despite challenges with conducting clinical trials in liposarcoma, preliminary results for several of these novel, biology-driven therapies are encouraging.
    Cancers 06/2013; 5(2):529-49. DOI:10.3390/cancers5020529
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    • "Moreover, animal model studies have verified the in vivo efficacy of TZDs (Table 4, ref. [96] [106] [109] [133] [134] [135]). Furthermore , the in vivo anticancer efficacy of troglitazone and rosiglitazone has been demonstrated in some patients with liposarcomas [127] [133] or prostate cancer [116] [136] [137]. In a phase II study of troglitazone on patients with histologically-confirmed prostate cancer, symptomatic metastasis was prevented [137]. "
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