RIP1/3 Kinases as New Targets in Malignant Mesothelioma

RIP1/3 激酶作为恶性间皮瘤的新靶点

基本信息

批准号：
8799710
负责人：
SIDDHARTH BALACHANDRAN
金额：
$ 41.47万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8799710
关键词：
Address Antineoplastic Agents Apoptosis Area Asbestos Asbestos-Related Malignant Mesothelioma Binding Biochemical Process Biological Response Modifiers Cell Death Cells Cessation of life Chemoprevention Chemopreventive Agent Chronic Complex Data Deposition Development Disease Disease Progression Drug Kinetics Environmental Exposure Etiology Event Exposure to FDA approved Fiber Gene Expression Genetic Genetically Engineered Mouse Goals Immune Immunology In Vitro Individual Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-18 Interleukin-6 Interleukins Malignant Neoplasms Malignant mesothelioma Mediating Mesothelial Cell Mesothelioma Modeling Molecular Mus Necrosis Pathogenesis Phosphotransferases Preclinical Testing Prevention Prevention approach Prevention therapy Preventive Production Property Protein Kinase RIPK3 gene Recording of previous events Relative (related person)Research Personnel Risk Role Seasons Site Source Staging Structure Synthesis Chemistry TNF gene Testing Therapeutic Treatment Efficacy aggressive therapy anakinra analog bcr-abl Fusion Proteins cell type chemotherapeutic agent chemotherapy design experience gene induction human RIPK1 protein human disease in vivo in vivo Model inhibitor/antagonist insight kinase inhibitor macrophage mouse model next generation novel pre-clinical prevent programs public health relevance research clinical testing research study therapy resistant tool tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Malignant mesothelioma is a devastating, therapy-resistant cancer most commonly seen in individuals with a history of exposure to asbestos. Asbestos is both a powerful inducer of necrotic death in mesothelial cells and a potent activator of pro-inflammatory gene expression in macrophages. As necrotic cells are themselves well- established inducers of inflammation, these two asbestos-induced events - necrosis in mesothelial cells and pro-inflammatory gene induction in macrophages - are believed to collaborate in an amplificatory cycle that eventually culminates in mesothelioma. We have made the exciting discovery that both asbestos-induced cell necrosis and inflammatory gene induction are dependent on two kinases, receptor-interacting protein (RIP) 1 and RIP3. Importantly, both RIP1 and RIP3 are druggable targets, and we have identified several potent RIP1/3 single- and dual-kinase inhibitors, including an FDA-approved anti-cancer drug, thus offering a unique opportunity for accelerated development of new chemopreventive and chemotherapeutic agents for malignant mesothelioma. We have also established cutting-edge murine models of RIP1 and RIP3 kinase deficiency, as well as an in vivo model of asbestos-driven mesothelioma progression that faithfully mimics the human disease. Together, these new inhibitors and mouse models of malignant mesothelioma allow us to set forth the following three goals for this proposal. First, we will identify the source (i.e., macrophages vs. non-phagocytic cells), relative contribution (RIP1 vs. RIP3), and stage (early vs. late) of pathogenic RIP1/3 kinase activity during asbestos-induced tumorigenesis. Second, we will evaluate activity and pharmacological properties of a panel of single- and dual-targeting RIP1/RIP3 inhibitors in vitro and select the most promising molecules for preclinical testing of RIP1/3 kinase blockade in mesothelioma. We will also determine the crystal structures of RIP1 and RIP3 in complex with a potent new RIP1/3 dual-kinase inhibitor to repurpose this inhibitor (a current FDA-approved anti-cancer agent) for use in mesothelioma. Third, we will test if inhibiting RIP1/3 kinase activity in vivo has preventiv and/or therapeutic efficacy in a preclinical mouse model of malignant mesothelioma. These multipronged studies, proposed by three highly experienced investigators with complementary expertise, represent a comprehensive approach bringing together immunology, genetics, and synthetic chemistry to yield both novel basic insights into mesothelioma development and translational opportunities in malignant mesothelioma prevention/therapy. Successful completion of these Aims has the potential to radically transform approaches for the prevention and treatment of this incurable cancer.

描述（由申请人提供）：恶性间皮瘤是一种毁灭性的、难以治疗的癌症，最常见于有石棉接触史的个体。石棉既是间皮细胞坏死性死亡的强大诱导剂，也是巨噬细胞中促炎基因表达的有效激活剂。由于坏死细胞本身就是公认的炎症诱导剂，因此石棉诱导的这两种事件——间皮细胞坏死和巨噬细胞中促炎基因诱导——被认为在一个放大循环中协同作用，最终导致间皮瘤。我们有了令人兴奋的发现，石棉诱导的细胞坏死和炎症基因诱导都依赖于两种激酶，即受体相互作用蛋白 (RIP) 1 和 RIP3。重要的是，RIP1和RIP3都是可药物靶标，我们已经鉴定了几种有效的RIP1/3单激酶和双激酶抑制剂，包括FDA批准的抗癌药物，从而为加速开发新的化学预防和化疗药物提供了独特的机会恶性间皮瘤药物。我们还建立了 RIP1 和 RIP3 激酶缺陷的尖端小鼠模型，以及忠实模拟人类疾病的石棉驱动间皮瘤进展的体内模型。这些新的抑制剂和恶性间皮瘤小鼠模型共同使我们能够为该提案提出以下三个目标。首先，我们将确定来源（即巨噬细胞与非吞噬细胞）、相对石棉诱导的肿瘤发生过程中致病性 RIP1/3 激酶活性的贡献（RIP1 与 RIP3）和阶段（早期与晚期）。其次，我们将在体外评估一组单靶点和双靶点 RIP1/RIP3 抑制剂的活性和药理学特性，并选择最有希望的分子用于间皮瘤 RIP1/3 激酶阻断的临床前测试。我们还将确定 RIP1 和 RIP3 与一种有效的新型 RIP1/3 双激酶抑制剂复合物的晶体结构，以重新利用该抑制剂（目前 FDA 批准的抗癌药物）用于治疗间皮瘤。第三，我们将测试体内抑制 RIP1/3 激酶活性是否对恶性间皮瘤临床前小鼠模型具有预防和/或治疗功效。这些多管齐下的研究由三位经验丰富、专业知识互补的研究人员提出，代表了一种将免疫学、遗传学和合成化学结合在一起的综合方法，以产生关于间皮瘤发展的新颖的基本见解和恶性间皮瘤预防/治疗的转化机会。成功实现这些目标有可能从根本上改变这种无法治愈的癌症的预防和治疗方法。