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. ? ? ?
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