Role of c-Met in SCLC and Potential for Novel Therapy

描述（由申请人提供）：小细胞肺癌（SCLC）的总体预后为6%，迫切需要新的治疗方法。以前，我们已经表明c-Met受体酪氨酸激酶可以是SCLC的重要治疗靶点。c-Met/HGF参与多种实体瘤的增殖、细胞运动和迁移、侵袭、血管生成和转移。以前，我们已经确定了c-Met的质膜（JM）和脑信号蛋白（Sema）结构域中的c-Met突变，并显示它们是功能获得性突变。利用C. elegans建模系统，我们表明JM结构域c-Met突变体引起与外阴相关的显著表型，并被尼古丁（香烟烟雾的重要组分，并与SCLC的发病机制有关）进一步激活。在我们最初的提议中，我们研究了原发性SCLC肿瘤组织，但尚未确定与转移性肿瘤组织（如淋巴结和远处转移）相比，原发性肿瘤组织中SCLC中c-Met的突变或扩增;这对研究很重要，因为SCLC具有高度转移性。我们还确定了针对c-Met的特异性抑制剂，目前已有多项I期临床试验。在我们的研究中，最近，我们已经确定c-Met可以被HGF激活，并且磷酸化形式可以定位于细胞核。在细胞核内，磷酸-c-Met可以与各种蛋白质相互作用，如拓扑异构酶-I和转录因子Pax 5。有趣的是，Pax 5在SCLC中表达而非非SCLC;而Pax 8在非SCLC中表达而非SCLC。我们现在表明Pax 5是SCLC中c-Met基因的转录因子。因此，为了进一步研究c-Met在小细胞肺癌中的作用，我们建议：1.确定c-Met在原发性与转移性SCLC中的表达、突变和扩增模式; 2.确定细胞核c-Met在小细胞肺癌中的作用; 3.确定SCLC中c-Met、Pax 5和拓扑异构酶-I的组合靶向。随着我们在确定c-Met/HGF轴在SCLC中的作用方面的初步成功，许多生物学和生化工具的开发以研究SCLC中的c-Met途径，以及对SCLC中c-Met的新观察，我们将对SCLC的生物学和治疗产生巨大影响。公共卫生相关性：小细胞肺癌（SCLC）是一种棘手的疾病，迫切需要新的靶点。我们已经确定c-Met受体酪氨酸激酶可以被激活、突变或扩增，并且可以穿梭到细胞核。在细胞核中，它与不同的蛋白质结合，如Pax 5和拓扑异构酶-I，拟议的研究将剖析其机制。最终，我们建议使用这些分子实现联合治疗。

DESCRIPTION (provided by applicant): Small cell lung cancer (SCLC) has an overall prognosis of 6%, and novel therapies are desperately needed. Previously, we had shown c-Met receptor tyrosine kinase can be an important therapeutic target in SCLC. c-Met/HGF has been shown to be involved in proliferation, cell motility and migration, invasion, angiogenesis and metastasis of many solid tumors. Previously, we had identified mutations of c-Met in the juxtamembrane (JM) and semaphorin (Sema) domains of c-Met, and showed them to be gain-of-function mutations. Using C. elegans modeling system, we show that the JM domain c-Met mutants cause a dramatic phenotype related to the vulva, and is further activated with nicotine (an important component of cigarette smoke, and implicated in the pathogenesis for SCLC). In our initial proposal, we had looked at primary SCLC tumor tissues, but had not determined the mutation or amplification of c-Met in SCLC in primary tumor tissue as compared to metastatic tumor tissue (such as lymph nodes and distant metastases); this would be important to study since SCLC is highly metastatic. We had also determined specific inhibitors against c-Met, for which there are now several Phase I clinical trials. In our investigations, most recently, we have identified that c-Met can be activated by HGF, and the phosphorylated form can localize to the nucleus. Within the nucleus, phospho-c-Met can interact with various proteins such as topoisomerase-I and the transcription factor Pax 5. Interestingly, Pax 5 is expressed in SCLC and not non-SCLC; whereas, Pax 8 is expressed in non-SCLC and not SCLC. We now show that Pax 5 is a transcription factor for the c-Met gene in SCLC. Thus, to further study the role of c- Met in SCLC, we would propose to: 1. Determine the expression, mutational and amplification patterns of c-Met in primary versus metastatic SCLC; 2. Determine the role of nuclear c-Met in SCLC; 3. Determine the combinatorial targeting of c- Met, Pax5, and Topoisomerase-I in SCLC. With our initial success in defining the role of c-Met/HGF axis in SCLC, development of a number of biological and biochemical tools to study the c-Met pathway in SCLC, and new observations for c-Met in SCLC, we will dramatically impact on the biology and therapy for SCLC. PUBLIC HEALTH RELEVANCE: Small cell lung cancer (SCLC) is a difficult disease and novel targets are desperately needed. We have identified that c-Met receptor tyrosine kinase can be activated, mutated, or amplified, and can shuttle to the nucleus. In the nucleus, it binds to different proteins such as Pax5 and topoisomerase-I, and the studies proposed will dissect out mechanisms for this. Ultimately, we propose to bring to fruition combination therapies using these molecules.