Malignant gliomas cause severe neurologic dysfunction, including language disorders, memory and cognitive loss, motor deficits, visual impairment, seizures and progressive disability. Patients with the most common type of glioma (glioblastoma multiforme) have a median survival of only 12-24 months. While neurological symptoms may be alleviated with surgery, malignant gliomas commonly recur due to continued growth of residual microscopic disease. Therefore, more effective adjuvant therapies are required for treatment of residual tumor present after surgery. We have observed that 70% of human gliomas express high molecular weight melanoma-associated antigen (HMW-MAA), a large cell-surface proteoglycan (PG) that interacts with the extracellular matrix (ECM). Monoclonal antibodies (mAb) raised against HMW-MAA are capable of inhibiting the growth of tumor cells. The overall hypothesis that we wish to address in this proposal is that passive immunotherapy with HMW-MAA-specific mAbs inhibit glioma growth and prolong survival in a clinically relevant animal brain tumor model. This is consistent with similar findings using blocking mAbs against EGFR (Erbitux) and HER2/neu (Herceptin) as reported specifically for gliomas.
The specific aims of this proposal are to test the hypotheses that: 1. HMW-MAA-specific mAb accumulates and is retained in cerebral gliomas at high concentrations in vivo. Using a highly sensitive technique (MicroPET), we will measure the accumulation and retention of HMW- MAA-specific mAb in GL261 murine cerebral gliomas following systemic administration. 2. HMW-MAA-specific mAb inhibits the growth of cerebral gliomas in vivo and prolongs the survival of mice with intracranial gliomas. We will measure the effect of HMW-MAA-specific mAb on tumor growth and survival in C57BL/6 mice with syngeneic GL261 cerebral gliomas. 3. HMW-MAA-specific mAb inhibits HMW-MAA-mediated signal transduction and tumor cell growth. We will measure the effect of HMW-MAA-specific mAb on tumor cell growth, survival and intracellular signaling in cultured GL261 cells and correlate these results with the effects of mAb on GL261 gliomas in vivo. These studies will be used to develop a rationale for focusing on a single HMW-MAA-specific mAb to humanize and develop for a Phase I clinical trial against human gliomas. This proposal fits with the overall goal of our research program which is centered on the development of targeted immunotherapeutic strategies to treat malignant gliomas. ? ?
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