Abstract 5391: Rosiglitazone and Gemcitabine combination therapy limits tumor progression and prolongs survival in pancreatic adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer related mortality with a dismal 2-5% 5-year survival rate because clinically apparent disease is usually detected late in disease progression and lacks effective therapies. The current ‘standard of care’ for pancreatic cancer patients is Gemcitabine, a deoxycytidine analog, which has been shown to increase quality of life and the median survival of patients by a few weeks. Although Gemcitabine therapy limits pancreatic tumor progression, PDA is often insensitive to chemotherapeutic agents, limiting their success and underlining the need for additional therapies which would enhance the efficacy of current treatments. We investigated combinations of Gemcitabine with drugs that target both the growing tumor and the immunosuppressive inflammatory microenvironment. Inflammation accompanies tumor progression in pancreatic cancer which can support tumor cell survival and growth directly, enhance tumor cell resistance to Gemcitabine and limit anti-tumor immune responses through induction of immunosuppressive mechanisms. Rosiglitazone Maleate, an FDA-approved drug for the treatment of type II diabetes, targets the PPARγ receptor, a major modulator of the inflammatory response. Rosiglitazone has been shown to limit tumor growth through effects on angiogenesis, differentiation and apoptosis. Additionally, some evidence suggests that PPARγ may regulate multi-drug resistance and may therefore limit tumor chemoresistance. We found that Rosiglitazone enhanced the efficacy of Gemcitabine by reducing tumor proliferation, limiting invasiveness, and enhancing tumor cell apoptosis in vitro. Therapeutic combination of Rosiglitazone and Gemcitabine was evaluated in subcutaneous and orthotopic models of pancreatic cancer, and revealed that the combination significantly reduced tumor progression and metastasis, enhanced tumor cell apoptosis in vivo and significantly extended overall survival compared to Gemcitabine alone. Together these results provide pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5391.