Abstract 1962: Dianhydrogalactitol (VAL-083) has a distinct mechanism of action that suggests combination with PARP inhibitors as an effective therapeutic strategy
Authors: Bacha Jeffrey A. , He Guangan , Steino Anne , Brown Dennis M. , Siddik Zahid H. 
Published: August 2018

Abstract
Ovarian cancer is usually treated with platinum (Pt)-based chemotherapy, but patients frequently develop Pt-resistance. Dysfunctional p53 is implicated in Pt-resistance, comprising a therapeutic challenge in high grade serous ovarian cancer (HGSOC), where p53 is 96% mutated. Attempts to overcome Pt-resistance in HGSOC include agents blocking the DNA repair pathways, most notably the PARP inhibitors (PARPi), leading to accumulation of DNA double strand breaks (DSBs) and cancer cell death. However, PARPi resistance often arises, leading to a 5-year survival rate of 40% in HGSOC. VAL-083 is a first-in-class DNA damaging agent with demonstrated clinical activity against a range of tumors, including ovarian. VAL-083 rapidly induces interstrand cross-links at guanine-N7 leading to DSBs, activation of the homologous recombination (HR) DNA repair pathway, S/G2 cell cycle arrest and cancer cell death. Notably, VAL-083 induces cell death through two parallel pathways; one p53-independent and one p53-dependent. We have shown that VAL-083 is able to overcome cisplatin resistance in a panel of ovarian cancer cells, independent of p53 status. We have also shown that VAL-083 maintains activity independent of DNA repair mechanisms such as O6-methylguanine DNA methyltransferase (MGMT), non-homologous end-joining (NHEJ) and mismatch repair (MMR), implicated in resistance to chemotherapeutics, including cisplatin and PARPi. Cancer cells thus rely heavily on functional HR for repair of VAL-083-induced DSBs, proposing combination therapy with agents further inducing DSBs or blocking their repair, including PARPi. Taken together, these data propose VAL-083 for treatment of Pt-resistant HGSOC and for combination therapy with PARPi. Here, we study the cytotoxicity of VAL-083 in combination with PARPi (olaparib, niraparib, rucaparib, veliparib or talazoparib) against HR-proficient and HR-impaired ovarian cancer cells, the impact of p53 status and Pt-resistance. VAL-083 cytotoxicity alone and in combination with PARPi was investigated using the MTT assay in HR-proficient and HR-impaired A2780 ovarian cancer cells. The impact of p53 status was studied by CRISPR/cas 9 knockout of p53 in wildtype A2780 cells and in a panel of p53-mutated ovarian cancer cells. We report increased VAL-083 cytotoxicity against HR-impaired A2780 cells. We further report superadditivity in both HR-proficient and HR-deficient A2780 cells between VAL-083 and olaparib, niraparib, talazoparib or rucaparib. In conclusion, our results demonstrated a distinct DNA damaging mechanism for VAL-083, resulting in the ability to overcome Pt-resistance, target HR-impaired tumors and overcome MGMT, MMR and NHEJ-related chemoresistance. In addition, VAL-083 activity was independent of p53 status and superadditive with PARPi in HR-proficient and HR-deficient A2780 tumor cells.
Citation Format: Jeffrey A. Bacha, Guangan He, Anne Steino, Dennis M. Brown, Zahid H. Siddik. Dianhydrogalactitol (VAL-083) has a distinct mechanism of action that suggests combination with PARP inhibitors as an effective therapeutic strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1962.