A novel combination therapy for the treatment of Pancreatic adenocarcinoma

描述（由申请人提供）：2008年将诊断出37,000多例新的胰腺腺癌（PDA），估计有34290例死亡，因为这种侵袭性疾病的5年生存率为2-5%。吉西他滨是目前胰腺癌患者的“标准治疗”，因为它已被证明可以提高患者的生活质量，并将患者的生存期延长几周。吉西他滨的抗肿瘤活性受到肿瘤细胞对凋亡的抵抗和肿瘤相关免疫抑制的严重限制，强调需要额外的治疗。吉西他滨与靶向细胞凋亡抵抗和免疫抑制机制的其他药物联合使用将增强吉西他滨的抗肿瘤活性。我们实验室对胰腺癌移植模型的观察表明，与单独使用吉西他滨相比，fda批准用于治疗II型糖尿病的药物——马酸罗格列酮（文迪雅，葛兰素史克）与吉西他滨协同作用，可以限制肿瘤进展、侵袭并提高总生存率。一项随机临床试验的荟萃分析显示，罗格列酮可激活增殖激活受体γ (PPAR)，可限制几种小鼠和人类细胞系的肿瘤生长，并与恶性肿瘤发病率显著降低相关，但此前尚未与吉西他滨在体内联合治疗胰腺癌。PPAR可能调节肿瘤细胞对凋亡的抵抗和免疫抑制？，解释吉西他滨对PPAR的体外疗效增加？激活。已发表的证据表明PPAR？调节AKT细胞存活通路，参与肿瘤细胞对吉西他滨的耐药。此外，PPAR？可能会限制促进免疫抑制性骨髓源性抑制细胞（MDSC）和T调节细胞（Tregs）的炎症介质，这些炎症介质伴随着胰腺癌的进展并限制吉西他滨的抗肿瘤活性。在该提案中，我们将：(1)验证和建立临床前数据，验证马来酸罗格列酮（文迪雅）和吉西他滨联合治疗是否限制了胰腺腺癌自发模型中的肿瘤进展和转移性传播，该模型与人类疾病非常相似；(2)确定罗格列酮是否通过调节AKT/PTEN细胞存活通路增强吉西他滨的疗效；(3)确定罗格列酮是否通过限制肿瘤相关的免疫抑制性MDSC和/或treg来增强吉西他滨的疗效。

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.