Design and Biological Activity of a Novel Urea Compound Against Glioblastoma [HK-390_scRNA-seq]

Despite advances in surgery and radiotherapy, glioblastoma (GBM) remains the deadliest adult brain cancer with unacceptable low median survival rates. Targeted therapies and biologics have failed to improve outcome and the standard-of-care against GBM has not changed in two decades. GBM, like many solid tumors are thought to be organized hierarchically with a small number of radiation- and chemotherapy-resistant glioma stem cells (GSCs) producing more differentiated progeny and can repopulate tumors after sublethal treatment.In this study we sought to develop novel compounds that cross the blood-brain barrier (BBB), target existing GSCs and interfere with glioma cell plasticity to prevent the induction of GSCs in response to irradiation. We show that novel urea compounds target existing GSCs, prevent the radiation-induced conversion of non-stem glioma cells into GSCs and prolong the median survival in mouse models of GBM with minimal normal tissue toxicity. HK-390 gliomaspheres were plated onto the Poly-D-Lysine/Laminin coated 6-well plate (#354595, Corning) and treated with MXC-017 at a concentration of 10 µM, one hour before receiving a single dose of 4 Gy the next day. Five days post-irradiation, the cells were collected for sequencing.