Development of New Therapeutics for Pancreatic Cancer Management

胰腺癌治疗新疗法的开发

基本信息

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
项目类别：
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&apos -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

项目摘要

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（由申请人提供）：胰腺癌是美国男性和女性癌症死亡的第四个主要原因。总体5年生存率小于5％，并且在很大程度上缺乏有效的疗法。手术切除是治愈的唯一机会，但大多数患者患有晚期，无法切除的疾病。迫切需要新的治疗策略。二甲双胍是一种广泛规定的药物，用作2型糖尿病的一线疗法，现在据报道在胰腺癌中具有抗肿瘤功效。二甲双胍的主要系统作用是降低血糖，但也降低了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激活抑制了下游MTORC1，该MTORC1整合了来自各种肿瘤细胞途径的信号以调节细胞的存活和生长。二甲双胍通过AMPK介导的MTORC1激活抑制胰腺癌的生长部分，但已知二甲双胍也破坏了胰岛素/IGF-1和GPCR信号通路和ERK之间的临界交叉序列。以及RAG GTPases和MTOR。实验室研究表明，二甲双胍明显抑制裸鼠中的人类胰腺癌细胞的生长。临床上的研究得到了临床前研究的支持，表明二甲双胍使用者患有胰腺癌的风险降低。二甲双胍的使用与糖尿病和胰腺癌患者的生存益处相关。但是，在某些研究中，中位生存期仅在二甲双胍使用者的癌症患者中延长了4个月。特别值得注意的是，二甲双胍的抗肿瘤作用通过药物剂量增加或静脉内给药增强。这些发现表明，可能需要发现二甲双胍的更有效的抗癌类似物，以提高临床益处和患者生存。因此，我们计划使用胰腺癌细胞模型设计，合成和检验二甲双胍的新类似物的抗肿瘤活性。非态细胞将用作对照。我们假设可以通过增强的抗癌活性和最少的非靶毒性来制备类似物。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。使用细胞增殖，凋亡，迁移/侵袭和潜在信号通路的测定法，将在体外评估类似物的抗肿瘤活性。这些临床前实验的反馈将用于修饰药物设计，以达到最佳的抗肿瘤功效和最小的毒性。将根据体外筛查测定法评估最佳抗肿瘤功效和靶向特异性，从而选择约2-3个候选药物进行体内研究。我们将在裸小鼠模型中使用人类胰腺癌细胞异种移植物来评估药物药代动力学的抗肿瘤活性和探索性研究。二甲双胍类似物的内分泌代谢作用也将在既定的胰岛素肥胖小鼠模型中在体内进行研究。在体内发现和验证二甲双胍类似物的有效抗肿瘤作用以及耐受性可能会导致及时的临床试验，并且可能在胰腺癌治疗方面取得了重大突破。