Abstract NT-109: VAL-083 (DIANHYDROGALACTITOL) SYNERGIZES WITH PARP INHIBITORS IN BRCA-PROFICIENT AND BRCA-DEFICIENT OVARIAN CANCER MODELS
Authors: Steino Anne , He Guangan , Bacha Jeffrey , Brown Dennis M. , Siddik Zahid H. 
Published: June 2021

BACKGROUND: Ovarian cancer is normally 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 carcinoma (HGSC), where p53 is universally mutated (96%). Attempts to overcome Pt-resistance in HGSC include agents blocking the DNA repair pathways, most notably the PARP inhibitors (PARPi), leading to the accumulation of DNA double strand breaks (DSBs) and cancer cell death. Sensitivity to PARPi is correlated with deficiencies in the homologous recombination (HR) DNA repair system, which is in charge of accurately repairing DSBs. BRCA1 and BRCA2 are key proteins in HR, and mutated BRCA1/2 (present in 20% of HGSC) are well-established biomarkers for PARPi sensitivity. PARPi treatment of Pt-sensitive gynecologic malignancies have improved progression free survival (PFS); however, improvements in overall survival have not been achieved and a 5-year survival rate of only 40% remains in ovarian cancer. Additionally, resistance to PARPi in the clinical setting is emerging as a significant medical challenge. VAL-083 is a first-in-class bifunctional DNA damaging agent with demonstrated clinical activity against a range of cancers, including ovarian. VAL-083 rapidly induces interstrand cross-links at guanine-N7 leading to DSBs, activation of the HR repair pathway 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 in vitro models, independent of p53 status. We have also shown that VAL-083 maintains activity independent of prominent DNA repair mechanisms such as O6-methylguanine DNA methyltransferase (MGMT), non-homologous end-joining (NHEJ) and mismatch repair (MMR) implicated in resistance to numerous chemotherapeutics, including cisplatin and PARPi. Cancer cells thus rely heavily on functional HR pathway for repair of VAL-083-induced DSBs. This suggests combination therapy with agents further inducing DSBs or blocking their repair, including PARPi. Taken together, these data propose VAL-083's potential for targeting Pt-resistant HGSC and for combination treatment with PARPi.

METHODS: In this study, we examined the cytotoxicity of VAL-083 in combination with PARPi (olaparib, niraparib, rucaparib, veliparib or talazoparib) against HR-proficient and HR-impaired ovarian cancer cells. VAL-083 cytotoxicity alone and in combination with PARPi was investigated using the 5-day MTT assay in HR-proficient (control siRNA) and HR-impaired (BRCA1 siRNA knockdown) A2780 ovarian cancer cells. RESULTS: We report increased VAL-083 cytotoxicity against HR-impaired A2780 cancer cells. We further report synergy between VAL-083 and PARPi olaparib, talazoparib and niraparib in both HR-proficient and HR-deficient settings. VAL-083 combination with rucaparib produced synergistic cytotoxicity in the HR-deficient setting, while VAL-083 combination with veliparib was no more than additive. These data demonstrate that VAL-083 can synergize with some PARP inhibitors in both a HR-proficient and HR-deficient setting.

CONCLUSION: Our results demonstrate a distinct DNA damaging mechanism for VAL-083, resulting in the ability to overcome cisplatin-resistance, target HR-impaired tumors and overcome MGMT, MMR and NHEJ-related chemoresistance. In addition, VAL-083 synergized with several PARPi, particularly olaparib, rucaparib and talazoparib, in both HR-proficient and HR-deficient ovarian tumor cells.

Citation Format: Anne Steino, Guangan He, Jeffrey Bacha, Dennis M. Brown and Zahid H. Siddik. VAL-083 (DIANHYDROGALACTITOL) SYNERGIZES WITH PARP INHIBITORS IN BRCA-PROFICIENT AND BRCA-DEFICIENT OVARIAN CANCER MODELS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-109.