ET-18VAL-083 IS A NOVEL N7 ALKYLATING AGENT THAT INHIBITS THE GROWTH OF GLIOMA STEM AND NON-STEM CULTURES, INCLUDING TEMOZOLOMIDE-RESISTANT LINES

The standard of care for glioblastoma multiforme (GBM) patients is surgical resection followed by temozolomide (TMZ) and radiation (XRT). TMZ is most effective for a minority of patients that exhibit epigenetic inactivation of 0-6-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme that removes the methyl-group adducts that are caused by TMZ. Thus, adducts that are not subject to the DNA repair mechanism of MGMT might provide additional benefit to GBM patients, the majority of which express MGMT and are TMZ-resistant, or acquire resistance after TMZ administration. The N7 alkylating agent, VAL-083, is not subject to MGMT mediated repair and might therefore be a more potent chemotherapeutic. VAL-083 is a first-in-class alkylating agent that crosses the blood brain barrier and is currently in clinical trials for glioma patients with recurrent disease. We have recently shown that cancer stem cells (CSC) and their paired non-CSC cultures derived from primary GBM tissues exhibit similar responses to TMZ, with this response dependent on the presence or absence of MGMT expression. We sought to investigate how our panel of stem and non-stem cultures responds to VAL-083 alone or in combination with XRT, and how the response would compare to TMZ. Cell cycle and cell viability analysis showed that VAL-083 has a measureable effect at low (1-5) micromolar doses in all cultures tested. Furthermore, the paired CSC and non-CSC cultures have similar responses to VAL-083, indicating that CSCs are not more resistant to VAL-083. At the doses used (5 µm and 2Gy, respectively), the combination of VAL-083 and XRT did not exhibit an additive effect on response in any of the cultures tested, though prior studies demonstrated/suggested VAL-083 has radiation-potentiating effects. Further experiments could elucidate a possible interaction. These results suggest that VAL-083 may provide a greater clinical benefit to glioma patients compared to TMZ.