A phase II trial with rosiglitazone in liposarcoma patients

Debrock, Guy; Vanhentenrijk, V; Sciot, Raf; Dębiec‐Rychter, Maria; Oyen, Raymond; Oosterom, A. Van

doi:10.1038/sj.bjc.6601306

Cited by 151 publications

(95 citation statements)

References 17 publications

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“…Unfortunately, a similar conclusion was drawn in a recent phase II trial using rosiglitazone in liposarcoma patients. In contrast to preliminary trials in which PPAR␥ ligands showed therapeutic promise, rosiglitazone was not an effective drug for the treatment of liposarcomas (Debrock et al 2003).…”

Section: Discussionmentioning

confidence: 71%

PPARγ signaling exacerbates mammary gland tumor development

Sáez¹,

Rosenfeld²,

Livolsi³

et al. 2004

Genes Dev.

173

148

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Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor ␥ (PPAR␥) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR␥ ligands. To evaluate the therapeutic potential of increased PPAR␥ signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR␥ in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPAR␥ potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPAR␥ signaling serves as a tumor promoter in the mammary gland. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, ligand-responsive transcription factors that participate in many important physiological processes . Mammals have three different PPARs (PPAR␣, PPAR␦, PPAR␥) that form functional heterodimers with the retinoid receptor RXR. These complexes are chief regulators of lipid storage and catabolism. Native and oxidized polyunsaturated fatty acids bind the PPARs and stimulate their transcriptional activity. The function of the PPARs is also modulated by arachidonic acid derivatives, such as prostaglandins and eicosanoids.PPAR␥ is the best-characterized member of the family. Its most prominent role is to regulate differentiation of cell types with active lipid metabolism, such as adipocytes and macrophage foam cells Walczak and Tontonoz 2002). The importance of this receptor in lipid homeostasis and energy balance is accentuated by the widespread use of thiazolidinediones (TZDs), synthetic PPAR␥ ligands, as antidiabetic drugs. The existence of FDA-approved PPAR␥ agonists and the ability of this receptor to induce cellular differentiation encouraged us to explore whether stimulation of PPAR␥ activity could curtail malignant cell growth, in analogy with what is observed with retinoic acid in acute promyelocytic leukemia.A survey of tumors revealed that PPAR␥ is generally overexpressed in liposarcoma, colon, breast, and prostate carcinoma (Tontonoz et al. 1997;DuBois et al. 1998). When treated with PPAR␥ and RXR ligands, cell lines derived from these neoplasms undergo morphological transformation and growth arrest in vitro (Tontonoz et al. 1997;Elstner et al. 1998;Kubota et al. 1998;Mueller et al. 1998;Sarraf et al. 1998). Additional cell culture studies have suggested that lung, pancreatic, and hematopoietic tumor cells also respond to thiazolidinedione treatment (Sporn et al. 2001). These observations prompted trials to evaluate PPAR␥ agonists as therapeutics in human liposarcoma, colon, breast, and prostate cancer...

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Section: Discussionmentioning

confidence: 71%

PPARγ signaling exacerbates mammary gland tumor development

Sáez¹,

Rosenfeld²,

Livolsi³

et al. 2004

Genes Dev.

173

148

View full text Add to dashboard Cite

show abstract

“…15 To date, clinical trials with the thiazolidinedione family of drugs have shown mixed results with respect to efficacy in the treatment of liposarcomas. 16,17 However, these studies included myxoid-round cell and pleomorphic liposarcomas and only two patients with dedifferentiated liposarcoma. Furthermore, the only consistent induction of PPAR-g responsive genes during therapy was in one of the dedifferentiated liposarcoma tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the only consistent induction of PPAR-g responsive genes during therapy was in one of the dedifferentiated liposarcoma tumors. 17 Subsequent studies suggested that mechanisms independent of PPAR-g activation mediated the antitumor effects of these drugs and stimulated more widespread interest in thiazolidinediones as cancer therapy. [30][31][32] Consequently, the efficacy of PPAR-g ligands on a variety of nonlipogenic malignancies was tested but, unfortunately, yielded little improvement in outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Therapy targeted against PPAR-g to induce liposarcoma differentiation and growth met with mixed success in early clinical trials. 16,17 Taken together, these data suggest that liposarcoma cells may retain the differentiation program controlled by PPAR-g in some tumors, whereas in others the program may be blocked during transformation or progression. Unlike MDM2 and CDK4, PPAR-g is abundantly expressed in benign adipocytes, so the presence of PPAR-g does not distinguish between benign and malignant adipose tumors.…”

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confidence: 88%

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Immunostaining for peroxisome proliferator gamma distinguishes dedifferentiated liposarcoma from other retroperitoneal sarcomas

et al. 2008

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“…37 However, these agents do not induce objective responses and there is no clinical benefit. 38 Additional in vitro studies have shown that PPARγ ligands induce growth arrest and apoptosis in a variety of cancer cells, including lung cancer cell lines. [39][40][41] However, clinical trials in breast, prostate, and colorectal cancer have also been disappointing.…”

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confidence: 99%