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生存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。HGF和c-Met越来越被视为有希望的治疗靶点，因为这些临床关联以及它们的多功能自分泌和旁分泌肿瘤促进活动，包括直接刺激肿瘤细胞生长、肿瘤细胞对细胞毒性治疗的抵抗、肿瘤细胞迁移/侵袭和肿瘤血管生成。我们已经证明，中和性抗HGF单克隆抗体（L2G7）特异性和有效地阻断HGF功能，抑制表达HGF的原位人类胶质瘤异种移植物的生长，包括原发性胶质瘤异种移植物，并延长动物存活时间。L2G7抑制胶质瘤Akt和map -激酶活性，抑制肿瘤血管生成、增殖指数，提高肿瘤凋亡指数。为了开发抗hgf单抗治疗恶性脑肿瘤的最佳方法，必须回答许多问题。未解决的问题包括- L2G7的最佳运输路线是什么？L2G7联合标准细胞毒治疗有什么好处？能否根据HGF:c-Met通路抑制的动态来优化联合疗法？我们能否确定对L2G7治疗或多或少有反应的胶质瘤亚群？本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问题和相关问题。我们的具体目标是：(1)确定抗HGF HuL2G7在异种胶质瘤移植中直接瘤内对流增强递送与全身递送的相对疗效；(2)确定HuL2G7是否能增强放射和/或化疗在异种胶质瘤移植中的疗效；(3)确定可用于预测胶质瘤对HGF:c-Met途径抑制敏感性/耐药性的临床可翻译的分子标记物。阳性结果将阐明抗HGF治疗的机制、给药方案和最佳开发抗HGF L2G7和潜在的其他HGF:c-Met途径抑制剂所必需的分子/生物反应标准。中枢神经系统癌研究结果也将大大有助于其他基于抗体的脑癌治疗方法的应用。肝细胞生长因子（HGF）是最常见的原发性中枢神经系统恶性肿瘤，如胶质母细胞瘤、髓母细胞瘤和脑转移瘤的治疗靶点。本研究将探讨如何最好地使用中和抗hgf单克隆抗体来抑制实验性脑肿瘤的生长。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抑制剂在脑肿瘤患者中的应用。

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.