Treatment of Liposarcomas Using a Combination of Thiazolidinediones and Retinoid X Receptor Selective Agonists

Inventors: Ron Evans, Peter Tontonoz, and Barry Forman
Potential Uses: Oncology, Drug Discovery and Development
Compositions useful for the treatment of liposarcomas

Liposarcoma is the most common soft tissue malignancy in adults, accounting for at least 20% of all sarcomas in this age group. Localized disease is treated primarily with surgery, often in combination with radiotherapy. Metastatic liposarcoma is associated with an extremely poor prognosis, with average five year survival ranging from 70% to 25%, depending on the type of tumor. The development of effective, noninvasive methods for treating liposarcomas would represent a significant advancement in the therapeutic arts. It has been discovered that PPAR-gamma is expressed consistently in each of the major histologic types of human liposarcoma. Maximal activation of PPAR-gamma with exogenous ligand (a thiazolidinedione or derivative thereof) promotes terminal differentiation of primary human liposarcoma cells, thereby blocking further proliferation. It has also been discovered that RXR-specific ligands are potent adipogenic agents in cells expressing the PPAR-gamma/RXR-alpha heterodimer and that simultaneous treatment of liposarcoma cells with a thiazolidinedionyl moiety (a PPAR-gamma-selective class of compounds) and an RXR-specific ligand results in an additive stimulation of differentiation. The invention includes compositions useful for the treatment of liposarcomas.