Inhibition of Migration for Treatment of Malignant Glioma

DESCRIPTION (provided by applicant): Malignant gliomas, the most common subtype of primary malignant brain tumors, are aggressive, highly invasive, and neurologically destructive tumors. Patients with glioblastoma (GBM) the most aggressive form, have a me dian survival ranging from 9 to 12 months, a fact that has changed little after years of research. Therapies used effectively in the treatment of other solid tumors are ineffective in the treatment of GBM. The ability of glioma cells to widely invade norma l brain tissue via cell migration is a key property of the malignant gliomas. Invasion and migration of glial cells results in clusters of tumor cells that are diffuse and infiltrative in contrast to other tumors where local spread is very limited. This in filtrative behavior of malignant glial cells also makes present treatment less effective; there is accumulating evidence that migrating tumor cells are less effected by anti- proliferative drugs and that they have an increased resistance to apoptosis. This reduces the efficacy of chemo- and radiation therapies. Thus, employing an anti-migration approach may circumvent mechanisms that cells employ to reduce drug efficacy. Despite this possibility, inhibition of cell migration has largely been ignored as a po tential approach to treating these malignancies. Motility Inc. has developed a small protein (LD22-4, 86 aa, 8400 MW) that has been proven to inhibit cell migration of a variety of tumor cells including malignant glioma as well as endothelial cells. The ap plication of LD22-4 in various animal models has demonstrated that it has the capacity to suppress tumor growth, even at the earliest stages before angiogenesis has occurred. This project will 1) test the ability of LD22-4 itself to suppress the early stag es of tumor growth and 2) determine whether inhibition of migration by treatment with LD22-4 increases the sensitivity of malignant glioma cells to Temozolomide. Project Narrative Survival of patients with malignant gliomas has remained essentia lly unchanged over the last few decades. With such slow progress being made in the development of new treatments, novel and more successful therapies are needed to increase the number and types of options available to physicians treating malignant glioma. The project outlined in this proposal tests the effectiveness of a newly developed protein that targets malignant glioma cells in a unique manner, the inhibition of cell migration, offering additional hope to patients with this deadly disease.