PDTM-27. DIANHYDROGALACTITOL (VAL-083) OVERCOMES CHEMORESISTANCE IN PEDIATRIC MALIGNANT BRAIN TUMORS AND DISPLAYS SYNERGY WITH TOPOISOMERASE INHIBITORS

摘要

More children die from brain cancer than from any other disease. Medulloblastoma (MB) and pediatric high-grade gliomas (pHGG) are the most common malignant brain cancers in children. Children with pHGG have few therapeutic options and 5-year survival is less than 20%. Treatment includes surgery, radiotherapy and various chemotherapeutic combinations often including topoisomerase inhibitors and/or temozolomide (TMZ). The expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is strongly correlated with TMZ-resistance and is highly expressed in many pHGG, and deficient DNA mismatch repair (MMR) (25% of pHGG) confers a secondary mechanism of TMZ-resistance. VAL-083 is a novel bi-functional DNA targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. In prior NCI-sponsored clinical trials, VAL-083 was well-tolerated and demonstrated activity against pediatric brain tumors, including pHGG and MB. VAL-083 induces interstrand cross-links at N7-guanine, DNA double-strand breaks and irreversible S/G2-phase cell cycle arrest leading to persistent activation of the homologous recombination (HR) DNA repair pathway and cancer cell death. VAL-083 overcomes MGMT-related resistance mechanisms and is equally active against HGG cancer stem cells and non-stem cells, in vitro. Here, we report strong VAL-083 activity against pHGG (SF188), MB (Med8a) and adult HGG (T98G) cancer cells known to be radio- and chemoresistant, independent of p53 and MGMT status. Further, VAL-083 cytotoxicity was shown to be MMR-independent in two colorectal cancer cell lines. We also report strong synergy between VAL-083 and inhibitors of both topoisomerase I and II (camptothecin and etoposide) in A549 and PC3 cancer cell lines. Our results suggest a distinct anti-cancer mechanism for VAL-083 compared to standard MB/pHGG chemotherapy, resulting in the ability to overcome MGMT- and MMR-related chemoresistance and exhibiting synergy with topoisomerase inhibitors.