ATPS-61NEW SMALL MOLECULES THAT KILL HYPOXICALLY TRANSFORMED GLIOMA STEM-LIKE CELLS

Abstract

High grade gliomas (HGGs) are lethal brain cancers, accounting for 78% of adult onset primary CNS malignancies. HGGs are resistant to current conventional therapies, including radiation therapy (RT), chemotherapy, and treatment with anti-angiogenic agents. Populations of cancer cells surviving these treatments regenerate leading to recurrence in more than 95% of patients. Spontaneous tumor necrosis within avascular tumor domains imparts poor clinical prognosis as glioma cells are reprogrammed by hypoxic transcription factors to adopt ‘stem-cell’ like properties; commonly referred to as glioma ‘stem-like’ cells (GSCs). GSCs possess several properties of normal stem cells, including self-aggregation, expression of stem cell markers, ability to survive in hypovascularized tumor regions, ability to survive detachment, and most importantly, the ability of tumor regrowth. GSCs can stop proliferating in hypoxic and acidic perinecrotic regions, which increases their resistance to RT and conventional anti-mitotic therapies. Hypoxically reprogrammed GSCs represent an important drug target to prevent the recurrence of HGGs. Drug targeting of hypovascularized GSCs is challenging as acidic and hypoxic tumor domains promote cell cycle arrest. Thus, therapeutic agents must be cytotoxic, not cytostatic, and need to kill independently of proliferative status. We developed novel small molecules that triggers ‘mis-trafficking’ of endosomes containing urokinase protein cargo in HGGs, and killing non-proliferating and proliferating glioma cells by an irreversible caspase-independent necrotic pathway. We identified that more than 90% of glioma cells within 22 patient derived xenografts (PDX) express intracellular PAI-1 and uPA and that 40-80% of these cells co-express the pluripotent stem cell transcription factors Oct4 and Nanog. Our lead small molecule crosses the intact rodent BBB and selectively kills glioma cells within intracerebral PDX glioma xenografts (PDX). The anti-glioma cytotoxicities of these small molecules is cell cycle independent, unaffected by hypoxia, and could represent an effective adjunctive therapy to be combined with radiotherapy, anti-mitotic, and/or anti-angiogenic therapies.