A novel combination therapy for the treatment of Pancreatic adenocarcinoma

治疗胰腺癌的新型联合疗法

• 批准号: 8333356
• 负责人: Michael A. Hollingsworth
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333356
• 关键词: AKT inhibition; American Cancer Society; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Applications Grants; Cancer Etiology; Cancer Patient; Cell Survival; Cessation of life; Clinical Data; Clinical Trials; Combined Modality Therapy; Data; Deoxycytidine; Diagnosis; Disease; Dose; Drug usage; FDA approved; Human Cell Line; Immune; Immunosuppression; In Vitro; Incidence; Inflammation; Inflammation Mediators; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Meta-Analysis; Modeling; Molecular Analysis; Mus; Myelogenous; Neoplasm Metastasis; Non-Insulin-Dependent Diabetes Mellitus; PPAR gamma; PTEN gene; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase I Clinical Trials; Pre-Clinical Model; Property; Proto-Oncogene Proteins c-akt; Publishing; Quality of life; Randomized Clinical Trials; Regulatory T-Lymphocyte; Reporting; Resistance; Rosiglitazone maleate; Schedule; Suppressor-Effector T-Lymphocytes; Survival Rate; Therapeutic; Therapeutic Agents; Time; Toxic effect; Transgenic Mice; Translating; Work; analog; base; chemotherapeutic agent; chemotherapy; design; dosage; drug mechanism; gemcitabine; human disease; immune resistance; improved; in vivo; in vivo Model; mortality; mouse model; neoplastic cell; novel; pancreatic neoplasm; pre-clinical; receptor; research study; rosiglitazone; standard of care; success; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）： 2008 年将诊断出超过 37,000 例新的胰腺癌 (PDA) 病例，估计死亡人数为 34,290 人，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“护理标准”，因为它已被证明可以提高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细胞凋亡的抵抗和肿瘤相关免疫抑制的严重限制，这突出表明需要额外的治疗。将吉西他滨与针对细胞凋亡抵抗和免疫抑制机制的其他药物相结合将增强吉西他滨的抗肿瘤活性。 我们实验室在胰腺癌移植模型中的观察表明，马来酸罗格列酮（文迪雅，葛兰素史克）是 FDA 批准的用于治疗 II 型糖尿病的药物，与单独使用吉西他滨相比，与吉西他滨具有协同作用，可限制肿瘤进展、侵袭并提高总体生存率。罗格列酮可激活增殖物激活受体γ（PPAR？），已被证明可以限制几种小鼠和人类细胞系中的肿瘤生长，并且在随机临床试验的荟萃分析中与显着降低的恶性肿瘤发病率相关，但之前尚未在体内与吉西他滨联合用于治疗胰腺癌。 肿瘤细胞对细胞凋亡和免疫抑制的抵抗力可能受到 PPAR? 的调节，这解释了吉西他滨对 PPAR? 的体外疗效增强。激活。已发表的证据表明 PPAR？调节 AKT 细胞存活途径，显示参与肿瘤细胞对吉西他滨的耐药性。此外，PPAR 具有显着的抗炎作用吗？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 (Treg) 的炎症介质，这些细胞伴随胰腺癌进展并限制吉西他滨的抗肿瘤活性。 在该提案中，我们将：（1）验证并建立关于马来酸罗格列酮（文迪雅）和吉西他滨的联合疗法是否在密切模仿人类疾病的自发性胰腺癌模型中限制肿瘤进展和转移性播散的临床前数据； (2)确定罗格列酮是否通过调节AKT/PTEN细胞存活途径来增强吉西他滨的疗效； (3) 并确定罗格列酮是否通过限制肿瘤相关免疫抑制性 MDSC 和/或 Tregs 来增强吉西他滨的功效。