Development of New Therapeutics for Pancreatic Cancer Management

胰腺癌治疗新疗法的开发

• 批准号: 8490000
• 负责人: Richard Joseph Pietras
• 金额: $ 16.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490000
• 关键词: 5' -AMP-activated protein kinase; Antineoplastic Agents; Apoptosis; Biguanides; Biological Assay; Blood Glucose; Cancer Etiology; Cancer Patient; Cell Proliferation; Cell Survival; Cell model; Cells; Cessation of life; Chemicals; Clinical; Clinical Trials; Cohort Studies; Data; Development; Diabetes Mellitus; Disease; Dose; Drug Design; Drug Kinetics; Drug usage; Endocrine; Excision; Feedback; GPCR Signaling Pathway; Growth; Guanosine Triphosphate Phosphohydrolases; Human; Hydrochloride Salt; Hyperinsulinism; Hypoglycemic Agents; In Vitro; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Laboratories; Laboratory Study; Lead; Malignant Epithelial Cell; Malignant neoplasm of pancreas; Mediating; Metabolic; Metformin; Modeling; Modification; Non-Insulin-Dependent Diabetes Mellitus; Non-Malignant; Normal tissue morphology; Nude Mice; Obese Mice; Operative Surgical Procedures; Pancreatic carcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phenformin; Preclinical Testing; Property; Reporting; Risk; Rodent Model; Signal Pathway; Signal Transduction; Specificity; Structure; Survival Rate; Testing; Tissues; Toxic effect; Unresectable; Validation; Woman; Work; Xenograft procedure; analog; analytical method; anticancer activity; base; cancer therapy; cell growth; conventional therapy; design; diabetes mellitus therapy; drug candidate; effective therapy; human FRAP1 protein; in vivo; men; migration; milligram; mouse model; neoplastic cell; novel; novel therapeutics; pancreatic cancer cells; pre-clinical; prevent; public health relevance; research study; response; screening

DESCRIPTION (provided by applicant): Pancreatic carcinoma is the fourth leading cause for cancer death in men and women in the US. The overall 5- year survival rate is less than 5%, and effective therapies are largely lacking. Surgical resection is the only chance at cure, but most patients present with advanced, unresectable disease. New therapeutic strategies are urgently needed. Metformin is a widely prescribed drug used as first-line therapy for diabetes mellitus type 2, and is now reported to have antitumor efficacy in pancreatic cancer. The primary systemic effect of metformin is to lower blood glucose, but it also reduces hyperinsulinemia associated with insulin resistance. At a cellular level, metformin stimulates AMP-activated protein kinase (AMPK). Metformin-induced activation of AMPK inhibits downstream mTORC1 which integrates signals from a diverse array of tumor cell pathways to regulate cell survival and growth. Metformin inhibits pancreatic cancer growth in part via AMPK-mediated inhibition of mTORC1 activation, but metformin is also known to disrupt critical cross-talk between insulin/IGF-1 and GPCR signaling pathways and ERK; as well as Rag GTPases and mTOR. Laboratory studies show that metformin markedly inhibits growth of human pancreatic cancer cells xenografted in nude mice. This preclinical work is supported by clinical cohort studies showing that metformin users have a reduced risk of pancreatic cancer; and that metformin use correlates with a survival benefit in patients with diabetes and pancreatic cancer. However, in some studies, median survival is only prolonged by 4 months in cancer patients who are metformin users. Of special note, antitumor effects of metformin are enhanced by increased drug doses or by IV administration. These findings suggest that discovery of more potent anticancer analogs of metformin may be needed to boost clinical benefit and patient survival. Thus, we plan to design, synthesize and test antitumor activity of new analogs of metformin using pancreatic cancer cell models. Nonmalignant cells will be used as controls. We hypothesize that analogs can be prepared with enhanced anticancer activity and minimal non- target toxicity. We will perform an extensive structure-activity study to investigate metformin analogs that have never been tested before. Antitumor activity of analogs will be evaluated in vitro using assays for cell proliferation, apoptosis, migration/invasion and underlying signaling pathways. Feedback from these preclinical experiments will be used to modify drug designs to achieve optimal antitumor efficacy and minimal toxicity. About 2-3 drug candidates will be selected for in vivo studies based on in vitro screening assays to assess optimal antitumor efficacy and target specificity. We will use human pancreatic cancer cell xenografts in nude mouse models to assess antitumor activity and exploratory study of drug pharmacokinetics. Endocrine- metabolic effects of metformin analogs will also be studied in vivo in an established insulin-resistant obese mouse model. Discovery and validation of potent antitumor action and tolerability of metformin analogs in vivo may lead to timely clinical trials and possibly a significant breakthrough in pancreatic cancer therapy.

描述(申请人提供)：胰腺癌是美国男性和女性癌症死亡的第四大原因。总的5年生存率不到5%，而且很大程度上缺乏有效的治疗方法。手术切除是治愈的唯一机会，但大多数患者都患有晚期不能切除的疾病。迫切需要新的治疗策略。二甲双胍是一种广泛用于2型糖尿病一线治疗的处方药，现在有报道称它对胰腺癌有抗肿瘤效果。二甲双胍的主要全身作用是降低血糖，但它也可以降低与胰岛素抵抗相关的高胰岛素血症。在细胞水平上，二甲双胍刺激AMP激活的蛋白激酶(AMPK)。二甲双胍诱导的AMPK激活抑制了mTORC1下游，mTORC1整合了来自不同肿瘤细胞通路的信号来调节细胞的生存和生长。二甲双胍抑制胰腺癌生长的部分途径是通过AMPK介导的抑制mTORC1激活，但众所周知，二甲双胍还可以干扰胰岛素/IGF-1和GPCR信号通路与ERK之间的关键串扰，以及RAG GTP酶和mTOR之间的相互作用。实验室研究表明，二甲双胍能显著抑制人胰腺癌细胞裸鼠移植瘤的生长。这项临床前工作得到了临床队列研究的支持，这些研究表明，使用二甲双胍的患者患胰腺癌的风险较低，并且二甲双胍的使用与糖尿病和胰腺癌患者的生存效益相关。然而，在一些研究中，使用二甲双胍的癌症患者的中位生存期仅延长了4个月。特别要注意的是，增加药物剂量或静脉注射可以增强二甲双胍的抗肿瘤作用。这些发现表明，可能需要发现更有效的抗癌类似物二甲双胍，以提高临床效益和患者存活率。因此，我们计划利用胰腺癌细胞模型设计、合成和测试新的二甲双胍类似物的抗肿瘤活性。非恶性细胞将作为对照。我们假设类似物的制备具有增强的抗癌活性和最小的非靶标毒性。我们将进行一项广泛的结构-活性研究，以研究以前从未测试过的二甲双胍类似物。类似物的抗肿瘤活性将在体外通过细胞增殖、细胞凋亡、迁移/侵袭和潜在的信号通路来评估。这些临床前实验的反馈将被用于修改药物设计，以实现最佳的抗肿瘤效果和最低的毒性。大约2-3个候选药物将被选择用于基于体外筛选试验的体内研究，以评估最佳的抗肿瘤疗效和靶标特异性。我们将使用人胰腺癌细胞裸鼠移植模型来评估其抗肿瘤活性，并对药物的药代动力学进行探索性研究。二甲双胍类似物的内分泌代谢效应也将在已建立的胰岛素抵抗肥胖小鼠模型中进行体内研究。在体内发现和验证二甲双胍类似物的强大抗肿瘤作用和耐受性，可能会导致及时的临床试验，并可能在胰腺癌治疗方面取得重大突破。