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.

项目总结/摘要 开发治疗胰腺癌的新方法是一项重大挑战。胰腺癌是一种 癌症是美国癌症相关死亡的第四大原因， 死亡/年胰腺癌治疗选择限于手术和/或以下治疗的组合： 化疗和放疗。不幸的是，胰腺癌的晚期诊断使得目前的治疗方法 无效。相对较新的靶向治疗的有效性仍有待证明。目前迫切 开发胰腺癌的选择性治疗的主要未满足的医疗需求。我们的新 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)有选择性地有效抑制一个键 分子途径总体目标是测试这种新型小分子作为抑制胰腺癌的抑制剂。 癌症进展的关键信号通路。化合物2是无毒的，药学上合适的， 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研究， 初步数据显示，我们有强有力的支持，2将在体内抑制胰腺癌的增殖。的新奇 该项目来自于所提出的抗胰腺癌化合物的独特可药用靶点。的 抑制单个分子通路可导致阻断胰腺炎三种机制假说 包括增殖、迁移和凋亡的癌症侵袭以及阻断化学抗性是新颖的。的 由于该小组的专门知识，拟议的工作可以很容易地完成。这项工作将分为 三个明确的目标。本工作的目的包括：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）为原位异种移植研究做准备，进行2项IND使能研究，3）进行疗效研究 2的研究，以显示对小鼠中原位PDAC细胞异种移植物的生长和病理学的抑制。结果 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。的 胰腺癌关键分子通路的无毒抑制剂的开发代表了一种新的 方法，并解决了一个主要的未满足的医疗需求，因为现有的方法的临床效用， 治疗人胰腺癌是有限的。我们假设先导化合物2会抑制胰腺癌的发生， 胰腺癌的体内原位异种移植动物模型中的癌增殖 从而提供了治疗胰腺癌的新治疗策略的可行性。