Development of New Therapeutics for Pancreatic Cancer Management

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大原因。总的5年生存率低于5%，并且缺乏有效的治疗方法。手术切除是治愈的唯一机会，但大多数患者表现为晚期，不可切除的疾病。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，目前有报道称其对胰腺癌具有抗肿瘤疗效。二甲双胍的主要全身作用是降低血糖，但也可减少与胰岛素抵抗相关的高胰岛素血症。在细胞水平，二甲双胍刺激AMP活化蛋白激酶（AMPK）。二甲双胍诱导的AMPK活化抑制下游mTORC 1，其整合来自多种肿瘤细胞途径的信号以调节细胞存活和生长。二甲双胍部分通过AMPK介导的mTORC 1激活抑制胰腺癌生长，但二甲双胍也已知会破坏胰岛素/IGF-1和GPCR信号通路与ERK之间的关键串扰;以及Rag GTP酶和mTOR。实验室研究表明，二甲双胍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，这些研究表明二甲双胍使用者患胰腺癌的风险降低;二甲双胍的使用与糖尿病和胰腺癌患者的生存获益相关。然而，在一些研究中，二甲双胍使用者的中位生存期仅延长4个月。特别值得注意的是，二甲双胍的抗肿瘤作用可通过增加药物剂量或IV给药增强。这些发现表明，可能需要发现更有效的二甲双胍抗癌类似物来提高临床获益和患者生存率。因此，我们计划使用胰腺癌细胞模型设计、合成和测试二甲双胍的新类似物的抗肿瘤活性。非恶性细胞将用作对照。我们假设可以制备具有增强的抗癌活性和最小的非靶毒性的类似物。我们将进行广泛的结构-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使用细胞增殖、凋亡、迁移/侵袭和潜在信号传导途径的测定在体外进行评价。来自这些临床前实验的反馈将用于修改药物设计，以实现最佳的抗肿瘤疗效和最小的毒性。将基于体外筛选试验选择约2-3种候选药物用于体内研究，以评估最佳抗肿瘤功效和靶点特异性。我们将在裸鼠模型中使用人胰腺癌细胞异种移植物来评估抗肿瘤活性和药物药代动力学的探索性研究。还将在已建立的胰岛素抵抗肥胖小鼠模型中研究二甲双胍类似物的内分泌代谢作用。二甲双胍类似物在体内的有效抗肿瘤作用和耐受性的发现和验证可能会导致及时的临床试验，并可能在胰腺癌治疗中取得重大突破。

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.