A novel combination therapy for the treatment of Pancreatic adenocarcinoma

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DESCRIPTION (provided by applicant): More than 37,000 new cases of pancreatic adenocarcinoma (PDA) will be diagnosed in 2008, with 34,290 estimated deaths, as this aggressive disease has a 2-5% 5-year survival rate. Gemcitabine is the current 'standard of care' for pancreatic cancer patients, as it has been shown to increase quality of life and extend patient survival by a few weeks. The anti-tumor activity of Gemcitabine is severely limited by tumor cell resistance to apoptosis and tumor-associated immune suppression, highlighting the need for additional therapies. Combining Gemcitabine with additional agents that will target apoptotic resistance and immune suppressive mechanisms will enhance the anti-tumor activity of Gemcitabine. Observations by our laboratory in a transplantable model of pancreatic cancer demonstrate that Rosiglitazone Maleate (Avandia, GlaxoSmithKline), an FDA-approved drug for the treatment of type II diabetes, synergizes with Gemcitabine to limit tumor progression, invasion and to increase overall survival compared to Gemcitabine alone. Rosiglitazone, which activates the proliferator-activated receptor gamma (PPAR?), has been shown to limit tumor growth in several murine and human cell lines and has been associated with a significantly lower incidence of malignancies in a meta-analysis of randomized clinical trials, but has not been previously combined with Gemcitabine in vivo for the treatment of pancreatic cancer. Tumor cell resistance to apoptosis and immune suppression may be modulated by PPAR?, explaining the increased in vitro efficacy of Gemcitabine upon PPAR? activation. Published evidence suggests PPAR? modulates the AKT cell survival pathway, shown to be involved in tumor cell resistance to Gemcitabine. Additionally, the significant anti-inflammatory effects of PPAR? may limit inflammatory mediators that promote immune suppressive myeloid-derived suppressor cells (MDSC) and T regulatory cells (Tregs), which accompany pancreatic cancer progression and limit the anti-tumor activity of Gemcitabine. In this proposal we will: (1) validate and establish pre-clinical data on whether the combination therapy of Rosiglitazone Maleate (Avandia) and Gemcitabine limits tumor progression and metastatic dissemination in a spontaneous model of pancreatic adenocarcinoma which closely mimics human disease; (2) determine whether Rosiglitazone enhances the efficacy of Gemcitabine through modulation of the AKT/PTEN cell survival pathway; (3) and determine whether Rosiglitazone enhances the efficacy of Gemcitabine by limiting tumor- associated immune suppressive MDSC and/or Tregs. PUBLIC HEALTH RELEVANCE: Treatment options for pancreatic adenocarcinoma are very limited and rarely curative and there is a need for novel therapies that enhance current chemotherapy treatments. Rosiglitazone, an FDA-approved drug used to treat type II diabetes, has been demonstrated in preliminary studies and other reports to decrease tumor growth and metastasis in several cancers and may be a beneficial drug in the treatment of pancreatic cancer. In this proposal, we will evaluate the success of combining Rosiglitazone with Gemcitabine for the treatment of pancreatic cancer, design an effective dosage and schedule of therapy, and examine the mechanisms by which these two therapeutic agents synergize to decrease pancreatic tumor progression.