Neutralizing Anti-HGF mAbs and CNS Malignancy

描述(申请人提供)：胶质瘤和许多其他实体恶性肿瘤的恶性进展和低存活率与跨膜受体酪氨酸激酶c-Met及其分泌配体肝细胞生长因子(HGF)的过度表达有关。由于HGF和c-Met的这些临床相关性及其多功能的自分泌和旁分泌促肿瘤活性，包括直接刺激肿瘤细胞生长、肿瘤细胞对细胞毒治疗的抵抗、肿瘤细胞的迁移/侵袭和肿瘤血管生成，HGF和c-Met越来越被视为有前途的治疗靶点。我们已经证明了中和抗HGF单抗(L2G7)特异性和有效地阻断了HGF的功能，并抑制了表达HGF的原位人脑胶质瘤移植瘤(包括原发胶质瘤移植瘤)的生长，延长了动物的生存时间。L2G7抑制胶质瘤Akt和MAP-K活性，抑制肿瘤血管生成、增殖指数，增加肿瘤细胞凋亡指数。为了更好地开发抗HGF单抗治疗恶性脑肿瘤，必须回答许多问题。尚未回答的问题包括：L2G7交付的最佳路径是什么？将L2G7与标准的细胞毒模式相结合有什么好处？能否根据HGF：C-Met途径抑制的动态变化来优化联合治疗？我们能确定对L2G7治疗有或多或少反应的胶质瘤亚群吗？这项研究将使用创新的异种移植模型系统，以及一系列互补的分子、生物学和成像肿瘤反应终点来回答这些和相关的问题。我们的具体目标是：(1)确定直接瘤内对流增强递送与系统递送抗HGF HuL2G7在胶质瘤异种移植瘤中的相对疗效，(2)确定HuL2G7是否增强了放射和/或化疗对胶质瘤移植瘤的疗效，以及(3)寻找临床可翻译的预测胶质瘤对HGF：C-Met途径抑制的敏感性/耐药性的分子标志物。阳性结果将阐明抗HGF疗法的机制、给药方案和分子/生物反应标准，这是以最佳方式开发抗HGF L2G7和潜在的其他HGF：C-Met途径抑制剂治疗中枢神经系统癌症所必需的。这些发现也将大大有助于将其他以抗体为基础的疗法应用于脑癌。肝细胞生长因子(HGF)是治疗胶质母细胞瘤、髓母细胞瘤和脑转移瘤等最常见的中枢神经系统恶性肿瘤的有效靶点。这项研究将研究如何最好地使用中和抗HGF单抗来抑制实验性脑瘤的生长。还将确定用于预测肿瘤敏感性和评估对HGF抑制的抗肿瘤反应的组织学、生化和遗传标记。结果将影响HGF抑制剂如何在脑瘤患者中使用。

DESCRIPTION (provided by applicant): Malignant progression and poor survival in glioma and many other solid malignancies are linked with over-expression of the transmembraneous receptor tyrosine kinase c-Met and its secreted ligand hepatocyte growth factor (HGF). HGF and c-Met are increasingly seen as promising therapeutic targets due to these clinical associations and to their multifunctional autocrine and paracrine tumor promoting activities that include the direct stimulation of tumor cell growth, tumor cell resistance to cytotoxic therapy, tumor cell migration/invasion, and tumor angiogenesis. We have shown that the neutralizing anti- HGF monoclonal antibody (L2G7) specifically and potently blocks HGF functions and inhibits the growth of HGF-expressing orthotopic human glioma xenografts, including primary glioma xenografts, and prolonged animal survival. L2G7 inhibits glioma Akt and MAP-kinase activity, tumor angiogenesis, proliferation index, and increases tumor apoptosis index. Numerous questions must be answered in order to optimally develop anti-HGF mAb therapy for malignant brain tumors. Unanswered questions include -What is the best route of L2G7 delivery? What are the benefits of combining L2G7 with standard cytotoxic modalities? Can combination therapies be optimized based on the dynamics of HGF:c-Met pathway inhibition? Can we identify subsets of gliomas that are more or less likely to respond to L2G7 therapy? This research will use innovative xenograft model systems, and an array of complementary molecular, biological, and imaging tumor response endpoints to answer these and related questions. Our specific aims are: (1) To determine the relative efficacy of direct intratumoral convection enhanced delivery vs. systemic delivery of anti-HGF HuL2G7 in glioma xenografts, (2) To determine if HuL2G7 enhances the efficacy of radiation and/or chemotherapy in glioma xenografts, and (3) To identify clinically translatable molecular markers for predicting glioma sensitivity/resistance to HGF:c-Met pathway inhibition. Positive results will elucidate mechanisms of anti- HGF therapeutics, dosing schemes, and molecular/biological response criteria necessary for optimally developing anti-HGF L2G7 and potentially other HGF:c-Met pathway inhibitors .for CNS cancer. Findings will also contribute substantially to the application of other antibody-based therapeutics to brain cancer. Hepatocyte growth factor (HGF) is a promising therapeutic target for the most common primary CNS malignancies such as glioblastoma and medulloblastoma and brain metastases. This research will examine how to best use a neutralizing anti-HGF monoclonal antibody to inhibit experimental brain tumor growth. Histological, biochemical, and genetic markers for predicting tumor sensitivity and assessing anti-tumor responses to HGF inhibition will also be determined. Results will impact on how HGF inhibitors are used in brain tumor patients.