Epigenetic changes and epigenetic therapy in retroperitoneal liposarcomas
Retroperitoneal liposarcomas are rare tumors and the only effective treatment is surgery. However, local recurrence is common after surgery and is the major cause of death. Due to the rarity of these tumors, little is known about the underlying abnormalities. Epigenetic changes, such as DNA methylation of promoter-associated CpG islands resulting in transcriptional silencing, are known to be frequent mechanisms of silencing tumor suppressor genes in most common human cancers. However, little is known about the epigenetic alterations in liposarcomas. DNA hypermethylation of tumor suppressor genes as p16 and Wnt pathway genes as APC has been described in small series of liposarcomas suggesting that epigenetic alterations may play an important role in pathogenesis of liposarcomas. Furthermore, a prior study suggested that epigenetic therapy may cause terminal differentiation of liposarcoma cell line to adipocytes. We hypothesize that epigenetic alterations occur frequently in liposarcomas and such alterations may be used to define prognostic biomarkers. Furthermore, we hypothesize that epigenetic therapy may have a role in treatment of liposarcomas. Our laboratory has experience in developing prognostic epigenetic markers and is currently testing epigenetic therapy in solid tumors in clinical trials. Moreover, our center has a high-volume multidisciplinary sarcoma team which provides a strong foundation for our proposed sarcoma research. In the current proposal, we plan to 1) Identify the epigenetic changes that occur frequently in retroperitoneal liposarcomas; 2) Identify biomarkers that predict survival and response to treatment in retroperitoneal liposarcomas; and 3) Test the efficacy of combination epigenetic therapy in vivo mouse models of liposarcoma. Our long-term goals are to understand the epigenetic changes that occur in retroperitoneal liposarcomas and define prognostic biomarkers as well as determine the utility of epigenetic therapy in sarcomas.