MOLECULAR MOTORS IN NEUROONCOLOGY

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Anaplastic gliomas are malignant neoplasms of the brain that remain frustratingly difficult to treat. The mean survival for the most malignant of these tumors-glioblastoma multiforme-is less than one year, and even the less aggressive members of this group of brain tumors generally kill their victims within 2-4 years. This state of affairs is due to the fact that anaplastic gliomas are relatively resistant to the effects of conventional radiation and chemotherapy-agents which inhibit a limited number of cellular targets. This in turn argues that other components of the glioma cell machinery which contribute to the malignant phenotype need to be identified and studied, in the hope of eventually developing methods that could inhibit their function and thus block this malignant behavior. It is the underlying hypothesis of this proposal that molecular motors, a class of enzymes that produce movement at the expense of ATP hydrolysis, represent such a component. These motors, whose importance in oncology has been underappreciated, are particularly important components in three elements of the malignant repertoire of gliomas-their ability to invade normal brain, their ability to generate a blood supply, and their ability to proliferate in an uncontrollable manner. Data will be presented which establishes that inhibiting one of these motors-myosin II-with non-toxic drugs blocks invasiveness, and that studying the molecular physiology of this motor protein yields new insights into how it works and is regulated. In this project, I will propose to: 1) study in greater detail the specific role(s) that myosin II plays in glioma invasion, and 2) examine the molecular basis for the regulation of myosin II activity. Methods will be developed that will test the feasibility of molecular genetic approaches to blocking the activity of myosin II in situ in glioma and endothelial cells. Data will also be presented to suggest that these approaches may also ultimately be applied to other molecular motors, such as the kinesins, that power the mitotic apparatus.