A novel combination therapy for the treatment of Pancreatic adenocarcinoma

描述(申请人提供)：2008年将诊断出超过37,000例新的胰腺癌(PDA)病例，估计有34,290人死亡，因为这种侵袭性疾病有2-5%的5年存活率。吉西他滨是目前胰腺癌患者的“标准护理”，因为它已被证明可以提高生活质量，并将患者的生存时间延长几周。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，突显了额外治疗的必要性。将吉西他滨与其他针对细胞凋亡抵抗和免疫抑制机制的药物相结合，将增强吉西他滨的抗肿瘤活性。我们实验室在可移植的胰腺癌模型中的观察表明，与单用吉西他滨相比，FDA批准的治疗II型糖尿病的药物马来酸罗格列酮(文迪雅，GlaxoSmithKline)与吉西他滨具有协同作用，可以限制肿瘤的进展、侵袭并提高总存活率。罗格列酮可激活增殖物激活受体γ(PPAR？)，已被证明在几种小鼠和人类细胞系中限制肿瘤生长，并在随机临床试验的荟萃分析中与显著降低的恶性肿瘤发生率有关，但以前尚未在体内与吉西他滨联合用于胰腺癌的治疗。PPAR？可能调节肿瘤细胞对凋亡和免疫抑制的抵抗，解释了吉西他滨提高PPAR？体外疗效的原因。激活。已公布的证据表明PPAR？调节AKT细胞的存活途径，表明它与肿瘤细胞对吉西他滨的耐药性有关。此外，PPAR的显著抗炎作用？可能会限制促进免疫抑制髓系衍生抑制细胞(MDSC)和T调节细胞(Tregs)的炎症介质，这些细胞伴随着胰腺癌的进展，并限制吉西他滨的抗肿瘤活性。在这项建议中，我们将：(1)验证并建立临床前数据，关于马来酸罗格列酮(文迪雅)和吉西他滨联合治疗是否在接近模拟人类疾病的自发胰腺癌模型中限制肿瘤的进展和转移转移；(2)确定罗格列酮是否通过调节AKT/PTEN细胞生存途径来增强吉西他滨的疗效；(3)以及确定罗格列酮是否通过限制肿瘤相关免疫抑制MDSC和/或Tregs来增强吉西他滨的疗效。 公共卫生相关性：胰腺癌的治疗选择非常有限，而且很少治愈，需要新的治疗方法来加强目前的化疗。罗格列酮是FDA批准的用于治疗II型糖尿病的药物，已在初步研究和其他报告中证明可以减少几种癌症的肿瘤生长和转移，可能是治疗胰腺癌的有益药物。在这项建议中，我们将评估罗格列酮和吉西他滨联合治疗胰腺癌的成功，设计有效的治疗剂量和治疗方案，并研究这两种治疗药物协同作用以减缓胰腺癌进展的机制。

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.