Novel Therapeutic Strategy for Gliomas

DESCRIPTION (PROVIDED BY APPLICANT): Malignant gliomas are characterized by their ability to swiftly and diffusely invade from their primary foci into the surrounding normal brain parenchyma, making them surgically incurable. The failure to control invasive subpopulations of cells may be the key cause of local glioma recurrence after radical tumor resection. Currently available therapeutic strategies have poor outcome and an effective solution may require attack on multiple aberrant mechanisms in these malignant cells. Onconova is developing novel, mechanism based, therapeutic agents that have differential effects on normal and cancer cells. The effect on cancer cells is pleiotropic and involves inhibition of cell growth as well as activation of apoptosis. Normal cells, such as endothelial cells involved in angiogenesis, are growth inhibited without induction of apoptosis. Our hypothesis is to screen this series of compounds that exhibit a broad range of effects on various genes that are involved in cell growth, invasion and angiogenesis. Preliminary data suggests that this strategy of impacting dual growth/death mechanisms with a small molecule drug is promising. The specific aims are 1) to expand the chemical structure and activity relationship of the drug and 2) to study the effect of Onconova Series compounds ON 01060, ON 01330, ON 01370, ON 01500, ON 01590 and ON 01910 on glioma growth, adhesion, migration and angiogenesis in in vitro models. The studies may provide valuable information about the role of these compounds in tumor cell adhesion, invasion and angiogenesis.