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

描述(申请人提供)：小细胞肺癌(SCLC)是一种侵袭性疾病，细胞毒性化疗似乎已经停滞不前。在小细胞肺癌中发现了许多异常的遗传事件，包括几种受体酪氨酸激酶(RTK)的过度表达。RTK是原癌基因，是细胞生长、分化、存活或运动的关键调节因子。RTK在小细胞肺癌中的作用刚刚开始被发现，我们建议特别研究c-Met。C-Met及其配体肝细胞生长因子(HGF)等受体可以旁分泌的方式影响SCLC细胞的生长，c-Met/HGF参与了其他实体瘤的增殖、细胞运动和迁移、侵袭、血管生成和转移。在各种实体肿瘤中发现了相当数量的c-Met突变，但到目前为止还没有在肺癌标本中进行研究。最具特征性的突变发生在遗传性肾细胞癌中，突变主要发生在酪氨酸激酶区域。我们建议研究c-Met在小细胞肺癌中的作用。利用10个单独的小细胞肺癌细胞系和32个来自小细胞肺癌患者的配对肿瘤标本，我们发现了c-Met(3/10细胞系和4/32肿瘤组织样本)的新突变，特别是在膜旁(JM)区域。C-Met中特定的JM结构域突变以前没有在小细胞肺癌或其他肿瘤中描述过。我们最近还发现c-Met/HGF通路在小细胞肺癌细胞系中具有功能，对细胞的运动和迁移有显著的影响。本研究的目的是确定c-Met突变在小细胞肺癌中的作用。此外，我们还将研究c-Met/HGF激活在小细胞肺癌中的意义，重点是细胞运动和迁移作为反映小细胞肺癌转移的指标。最后，我们将利用我们已经获得的c-Met的小分子抑制剂来确定这一途径是否可以作为小细胞肺癌的治疗靶点，最终目标是将这些分子带入临床试验。

DESCRIPTION (provided by applicant): Small cell lung cancer (SCLC) is an aggressive illness, for which cytotoxic chemotherapy appears to have plateaued. A number of abnormal genetic events have been identified in SCLC, including overexpression of several receptor tyrosine kinases (RTKs). RTKs are proto-oncogenes, and are key regulators for cell growth, differentiation, survival or motility. The role of RTKs has just begun to be identified in SCLC and we would like to propose to study c-Met in particular. SCLC cell growth can be influenced in a paracrine fashion with receptors such as c-Met and its ligand hepatocyte growth factor (HGF) produced by stromal cells, c- Met/HGF has been shown to be involved in proliferation, cell motility and migration, invasion, angiogenesis and metastasis in other solid tumors. There are a considerable number of mutations identified for c-Met in a variety of solid tumors, however none to date have been investigated in lung cancer specimens. The best characterized mutations are in hereditary renal cell carcinoma and the mutations are mainly in the tyrosine kinase domains. We propose to study the role of c-Met in SCLC. Utilizing 10 separate SCLC cell lines and 32 paired tumor specimens from patients with SCLC, we have identified novel mutations in c-Met (3/10 cell lines and 4/32 tumor tissue samples), especially in the juxtamembrane (JM) domain. The specific JM domain mutations in c-Met have not been previously described in SCLC or other tumors. We have recently also shown the c-Met/HGF pathway to be functional in SCLC cell lines, with dramatic effects on cell motility and migration. The goal of this proposal is to determine the role of the mutations of c-Met in SCLC. Also, we will study the implications of c-Met/HGF activation in SCLC with emphasis on cell motility and migration as a reflection of metastasis of SCLC. Finally, we will utilize small molecule inhibitors that we have obtained of c- Met to determine if this pathway can be therapeutically targeted in SCLC with the eventual goal of bringing these molecules to clinical trials.