RIP1/3 Kinases as New Targets in Malignant Mesothelioma

描述（由申请人提供）：恶性间皮瘤是一种毁灭性的，治疗抵抗性癌症，最常见于有石棉暴露史的个体。天冬氨酸既是间皮细胞坏死性死亡的强有力诱导剂，又是巨噬细胞促炎基因表达的有效激活剂。由于坏死细胞本身是公认的炎症诱导物，因此这两种石棉诱导的事件-间皮瘤细胞中的坏死和巨噬细胞中的促炎基因诱导-被认为在最终在间皮瘤中达到高潮的扩增循环中协作。我们已经取得了令人兴奋的发现，石棉诱导的细胞坏死和炎症基因诱导都依赖于两种激酶，受体相互作用蛋白（RIP）1和RIP 3。重要的是，RIP 1和RIP 3都是药物靶点，我们已经确定了几种有效的RIP 1/3单激酶和双激酶抑制剂，包括FDA批准的抗癌药物，从而为加速开发恶性间皮瘤的新化学预防和化疗药物提供了独特的机会。我们还建立了RIP 1和RIP 3激酶缺陷的尖端小鼠模型，以及石棉驱动的间皮瘤进展的体内模型，忠实地模拟了人类疾病。总之，这些新的抑制剂和恶性间皮瘤的小鼠模型使我们能够为这项提议提出以下三个目标。首先，我们将识别源（即，巨噬细胞与非吞噬细胞），相对 贡献（RIP 1与RIP 3）和阶段（早期与晚期）的致病性RIP 1/3激酶活性在石棉诱导的肿瘤发生。其次，我们将评估一组单靶向和双靶向RIP 1/RIP 3抑制剂的体外活性和药理学特性，并选择最有前途的分子用于间皮瘤RIP 1/3激酶阻断的临床前测试。我们还将确定RIP 1和RIP 3与一种有效的新型RIP 1/3双激酶抑制剂复合的晶体结构，以重新利用这种抑制剂（目前FDA批准的抗癌药物）用于间皮瘤。第三，我们将在恶性间皮瘤的临床前小鼠模型中测试体内抑制RIP 1/3激酶活性是否具有预防和/或治疗功效。这些多管齐下的研究，由三位经验丰富的研究人员提出，具有互补的专业知识，代表了一种综合的方法，将免疫学，遗传学和合成化学结合在一起，以产生对间皮瘤发展的新的基本见解和恶性间皮瘤预防/治疗的转化机会。这些目标的成功实现有可能从根本上改变预防和治疗这种无法治愈的癌症的方法。

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.