Novel Small Molecule Therapeutics for Pancreatic Cancer

项目摘要/摘要 开发治疗胰腺癌的新方法是一个巨大的挑战。胰腺癌是 美国癌症相关死亡的第四大原因，估计有3.7万人死亡 死亡人数/年。胰腺癌的治疗选择仅限于手术和/或联合 化疗和放射治疗。不幸的是，胰腺癌的晚期诊断提供了目前的治疗方法 效果不佳。相对较新的靶向治疗的有效性仍有待证明。有一件急事 开发胰腺癌选择性治疗的主要未得到满足的医疗需求。我们的新产品 治疗胰腺癌的方法是完全不同的，重点是抑制一个关键的分子途径。 我们已经发现并优化了一种小分子(即，2)，它可以选择性地、有效地抑制一个键 分子途径。总体目标是测试这种新的小分子作为抑制胰腺的抑制剂。 通过靶向一个关键的信号通路来促进癌症的进展。化合物2无毒，药学上适用 用于体内应用，并具有新的作用机制。基于广泛的体外和体内实验 初步数据显示，我们有很强的证据支持2会抑制胰腺癌体内增殖。的新奇之处 这个项目来自于拟议的抗胰腺癌化合物的独特的可药物靶点。这个 假设抑制单个分子通路可以导致阻断胰腺的三种机制 肿瘤的侵袭包括增殖、迁移和凋亡，以及阻断化疗耐药，是一种新的肿瘤侵袭方式。这个 由于团队的专业知识，拟议的工作可以很容易地完成。这项工作将分为 三个明确的具体目标。这项工作的目的包括：1)证明先导化合物2具有 有效抑制胰腺导管腺癌细胞模型增殖和迁移的能力 (PDAC)，2)对2进行IND使能研究，为原位异种移植研究做准备，以及3)DO疗效 研究2显示对小鼠原位PDAC细胞异种移植的生长和病理学的抑制。结果是 将进行总结。 所获得的结果将为治疗胰腺癌的新方法提供基本信息。这个 开发无毒的胰腺癌关键分子通路抑制剂代表着一种新的 方法并解决了一个主要的未得到满足的医疗需求，因为可用方法的临床效用 治疗人类胰腺癌是有限的。我们假设先导化合物2会抑制胰腺 微侧原位移植胰腺癌动物模型中肿瘤增殖的研究 从而为治疗胰腺癌提供一种新的治疗策略的可行性。

Project Summary/Abstract Developing new ways to treat pancreatic cancer is a significant challenge. Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and results in an estimated 37,000 deaths/year. Pancreatic cancer therapeutic options are limited to surgery and/or combinations of chemotherapy and radiation. Unfortunately, late-stage diagnosis of pancreatic cancer renders current therapies ineffective. The effectiveness of relatively new targeted treatments remains to be shown. There is an urgent major unmet medical need for the development of selective treatments for pancreatic cancer. Our new approach to pancreatic cancer is completely different and focuses on inhibition of a key molecular pathway. We have discovered and optimized a small molecule (i.e., 2) that selectively and potently inhibits a key molecular pathway. The overall Goal is to test this novel small molecule as an inhibitor to suppress pancreatic cancer progression by targeting a key signaling pathway. Compound 2 is non-toxic, pharmaceutically suitable for in vivo applications, and possesses a novel mechanism of action. Based on extensive in vitro and in vivo preliminary data, we have strong support that 2 will inhibit pancreatic cancer proliferation in vivo. The novelty of this project comes from the unique druggable target of the proposed anti-pancreatic cancer compound. The hypothesis that inhibition of a single molecular pathway can result in blocking three mechanisms of pancreatic cancer invasion including proliferation, migration and apoptosis and also block chemoresistance is novel. The proposed work can be readily accomplished because of the expertise of the team. The work will be divided into three straightforward Specific Aims. The Aims of the work include: 1) Show that lead compound 2 has the ability to potently inhibit proliferation and migration of cell models of pancreatic ductal adenocarcinomal (PDAC), 2) Do IND-enabling studies of 2 in preparation for an orthotopic xenograft study and 3) Do efficacy studies of 2 to show inhibition of growth and pathology of orthotopic PDAC cell xenografts in mice. The results will be summarized. The results obtained will afford fundamental information about a new approach to treat pancreatic cancer. The development of non-toxic inhibitors of molecular pathways crucial to pancreatic cancer represents a novel approach and addresses a major unmet medical need because the clinical utility of available approaches for treating human pancreatic cancer is limited. We hypothesize that lead compound 2 will inhibit pancreatic cancer proliferation in an in vivo orthotopic xenograft animal model of pancreatic cancer with minimal side effects and thus provide feasibility of a novel therapeutic strategy to treat pancreatic cancer.