Novel Small Molecule Therapeutics for Pancreatic Cancer

胰腺癌的新型小分子疗法

• 批准号: 8647088
• 负责人: John R Cashman
• 金额: $ 24.06万
• 依托单位: CHEMREGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647088
• 关键词: Acute; Address; Adverse effects; Animal Model; Apoptosis; Binding; Bioavailable; Cancer Biology; Cancer Center; Cancer Etiology; Cancer cell line; Cell Line; Cell Proliferation; Cell Survival; Cell model; Cells; Cessation of life; Chemicals; Clinical; Colon; Combination Drug Therapy; Control Animal; DNA biosynthesis; Data; Development; Diagnosis; Dose; Ductal; Effectiveness; Gene Expression; Genes; Goals; Growth; Human; In Vitro; Inhibitory Concentration 50; Lead; Lethal Dose 50; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Medical; Medical Research; Metabolic; Methods; Molecular; Mus; Nuclear; Operative Surgical Procedures; Pancreas; Pathology; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Preparation; Property; Protein Kinase; Proteins; Radiation; Research Institute; Scientist; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staging; TCF7L2 gene; Testing; Therapeutic; Toxic effect; Toxicology; Tumor Weights; Tyrosine Kinase Inhibitor; United States; Work; Xenograft procedure; base; cancer cell; drug development; gemcitabine; homeodomain; in vivo; inhibitor/antagonist; innovation; migration; novel; novel strategies; novel therapeutics; public health relevance; research study; small molecule; success; tumor; tumor growth; tumor progression

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.

项目摘要/摘要 开发治疗胰腺癌的新方法是一个重大挑战。胰腺癌是 美国与癌症相关死亡的第四个主要原因，估计估计37,000 死亡/年。胰腺癌治疗选择仅限于手术和/或组合 化学疗法和放射线。不幸的是，胰腺癌的后期诊断使当前疗法 无效。相对较新的目标治疗的有效性尚待显示。有紧急 对胰腺癌选择性治疗的开发的主要未满足医疗需求。我们的新 胰腺癌的方法是完全不同的，并且集中于抑制关键分子途径。 我们发现并优化了一个小分子（即2），该分子有选择地抑制钥匙 分子途径。总体目标是测试这个新颖的小分子作为抑制剂以抑制胰腺 通过靶向关键信号途径，癌症进展。化合物2是无毒的，在药物上适当的 用于体内应用，并具有一种新颖的作用机理。基于大量体外和体内 初步数据，我们有强烈的支持，即2将抑制体内胰腺癌的增殖。新颖的 该项目来自拟议的抗胰腺癌化合物的独特可药物目标。这 假设抑制单个分子途径可能会导致阻塞胰腺的三种机制 癌症入侵，包括增殖，迁移和凋亡以及阻断化学抗性是新颖的。这 由于团队的专业知识，可以很容易地完成建议的工作。工作将分为 三个直接的特定目标。工作的目的包括：1）表明铅化合物2具有 能够有效抑制胰腺导管腺癌的细胞模型的增殖和迁移 （PDAC），2）对2个对原位异种移植研究的准备，并进行2个研究，3）做功效 2显示了对小鼠原位PDAC细胞异种移植物的生长和病理的抑制作用的研究。结果 将总结。 获得的结果将提供有关治疗胰腺癌的新方法的基本信息。这 对胰腺癌至关重要的分子途径的无毒抑制剂的发展代表了一种新颖的 方法并满足了主要未满足的医疗需求，因为可用方法的临床实用性 治疗人胰腺癌是有限的。我们假设铅化合物2将抑制胰腺 胰腺癌的体内原位异种移植动物模型中的癌症增殖，最小的侧面 影响，从而提供了一种新型治疗策略来治疗胰腺癌的可行性。