Abstract B252: The unique mechanism of action of VAL-083 may provide a new treatment option for some chemo-resistant cancers.

Abstract

Abstract Poor outcomes in cancer therapy due to chemo-resistance remain a significant unmet clinical problem for many solid tumors and leukemias. VAL-083 (dianhydrogalactitol) represents a structurally unique first-in-class N7-bifunctional DNA alkylating agent. VAL-083 primarily mediates guanine N7 DNA cross-links, which separates it from other DNA alkylating chemotherapeutics (e.g. temozolomide) that have their primary cytotoxicity by targeting DNA at the O6 position of guanine. As expected from its mechanism, VAL-083 overcomes resistance associated with O6-methylguanine-DNA methyltransferase (MGMT) overexpression in vitro. Furthermore, unlike other N7-acting drugs, such as cisplatin which primarily induces intrastrand crosslinks, VAL-083 mediates interstrand DNA crosslinks. When tested side-by-side in a standard syngeneic mouse fibrosarcoma model (RIF-1 cell-line in C3H mice), VAL-083 demonstrated superiority to cisplatin in tumor growth delay. For mice treated with a single injection of cisplatin of 4 mg/kg, the tumor growth delay was 1.45 days compared to untreated controls. Single IP injection of VAL-083 at a dose of 10 mg/kg delayed tumor growth by 5.6 days. Combination treatment of VAL-083 followed immediately by cisplatin produced a more than additive effect by delaying growth 8.65 days. VAL-083 readily crosses the blood-brain barrier, accumulates in brain tissue and is effective against brain tumor cells both in vitro and in vivo, and against brain cancer stem cells in vitro. VAL-083 is currently in Phase I/II clinical trials for glioblastoma and recurrent metastatic brain tumors. Studies are underway to further characterize the efficacy of VAL-083 in various tumor cell-lines resistant to chemotherapy. Previous clinical studies showing VAL-083 activity in several tumor models, combined with the new data on MGMT-chemo-resistance and synergy with cisplatin makes VAL-083 a promising alternative for both primary and secondary brain tumors as well as cisplatin-resistant tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B252. Citation Format: Anne Steino, Jeffrey A. Bacha, William J. Garner, Sarath Kanekal, Zahid H. Siddik, Dennis M. Brown. The unique mechanism of action of VAL-083 may provide a new treatment option for some chemo-resistant cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B252.