Dddr-31. targeting cancer stem cells with a cdk2 inhibitor in glioblastoma

Abstract Glioblastoma (GB) is the most common and aggressive adult brain tumor with no cure. Brain tumor stem cells (BTSCs) are a rare population of self-renewing multipotent stem cells in GB that contribute to tumorigenesis, therapeutic resistance and tumour recurrence. Here, we report a CDK2 inhibitor that suppresses BTSCs via OSM/OSMR/STAT3 signalling pathway. To begin with we performed high throughput screening (HTS) of ~8400 compounds including FDA-approved drugs in patient derived human BTSCs that naturally harbour EGFRvIII mutation and elevated STAT3 phosphorylation, in search of compounds that can suppress EGFRvIII/OSMR/STAT3 oncogenic pathway. The screen led to the identification of a panel of CDK inhibitors that possessed important characteristics including a) ability to cross the blood-brain barrier with mall molecular weights of 277-566 kDa, b) low Topological Polar Surface Area (TPSA) of 76-115 A°, c) a low number of Hydrogen Bond Donors (HBDs) (1-4), and d) cLogP values ranging from 2-4. Following counter screens, we focused on a CDK2 inhibitor that significantly and most efficiently reduced OSM/OSMR signalling and STAT3 activation. Importantly, we found that the compound inhibited the self-renewal and growth of BTSCs in EGFRvIII subtype of BTSCs. This research has led to future investigation on in vivo assessment of this CDK2 inhibitor in combination with ionizing radiation and chemotherapy in preclinical models of GB.