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）是一种侵袭性疾病，细胞毒性化疗似乎已趋于稳定。已经在SCLC中鉴定了许多异常遗传事件，包括几种受体酪氨酸激酶（RTK）的过表达。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。RTKs在SCLC中的作用刚刚开始被确定，我们想特别建议研究c-Met。SCLC细胞生长可以以旁分泌方式受到受体如c-Met及其配体肝细胞生长因子（HGF）的影响，所述受体由基质细胞产生。c-Met/HGF已显示参与其它实体瘤中的增殖、细胞运动性和迁移、侵袭、血管生成和转移。在各种实体瘤中发现了相当数量的c-Met突变，但迄今为止尚未在肺癌标本中进行研究。最具特征的突变是遗传性肾细胞癌，突变主要在酪氨酸激酶结构域。我们建议研究c-Met在SCLC中的作用。利用10个单独的SCLC细胞系和32对来自SCLC患者的肿瘤标本，我们已经鉴定了c-Met中的新突变（3/10个细胞系和4/32个肿瘤组织样本），特别是在胞膜（JM）结构域中。c-Met中的特定JM结构域突变先前未在SCLC或其他肿瘤中描述。我们最近还显示c-Met/HGF途径在SCLC细胞系中是功能性的，对细胞运动性和迁移具有显著影响。该提案的目标是确定c-Met突变在SCLC中的作用。此外，我们将研究c-Met/HGF激活在SCLC中的影响，重点是细胞运动和迁移作为SCLC转移的反映。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该途径是否可以在SCLC中进行治疗靶向，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.