Abstract P053: VAL-083 (dianhydrogalactitol) synergizes with PARP inhibitors in BRCA-proficient and BRCA-deficient ovarian cancer models
Authors: Steino Anne , He Guangan , Zhai Beibei , Bacha Jeffrey , Brown Dennis M. , Daugaard Mads , Siddik Zahid H. 
Published: December 2021

Abstract
Platinum (Pt)-based chemotherapy plays a key role in ovarian cancer treatment, but patients frequently develop Pt-resistance. Dysfunctional p53 is implicated in Pt-resistance, comprising a therapeutic challenge in high grade serous ovarian carcinoma (HGSOC), where p53 is universally mutated. Attempts to overcome Pt-resistance in HGSOC include agents blocking the DNA repair pathways, most notably PARP inhibitors (PARPi), leading to 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 accurately repairs DSBs. BRCA1 and BRCA2 are key proteins in HR, and mutated BRCA1/2 are well-established biomarkers for PARPi sensitivity. PARPi treatment of Pt-sensitive ovarian cancers have improved progression free survival; however, improvements in overall survival have not been achieved and a 5-year survival rate of 40% remains in ovarian cancer. Additionally, resistance to PARPi has emerged as a significant clinical 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. VAL-083 is able to overcome cisplatin-resistance in a panel of ovarian cancer in vitro models. We have also shown that VAL-083 maintains activity independent of prominent DNA repair mechanisms implicated in resistance to numerous chemotherapeutics including cisplatin and PARPi such as MGMT, non-homologous end-joining and mismatch repair. Cancer cells thus rely heavily on a functional HR pathway for repair of VAL-083-induced DSBs. This rationalizes VAL-083 combination therapy with agents inducing DSBs or blocking their repair, including PARPi. Taken together, these data highlight VAL-083's potential for targeting Pt-resistant HGSOC in combination with PARPi. METHODS: The cytotoxicity of VAL-083 in combination with PARPi (olaparib, niraparib, rucaparib, veliparib or talazoparib) against HR-impaired (BRCA siRNA knockdown) and HR-proficient (control siRNA) ovarian cancer cells was studied. RESULTS: We report increased VAL-083 cytotoxicity against HR-impaired A2780 cancer cells. In addition, synergy between VAL-083 and olaparib, talazoparib and niraparib in both HR-proficient and deficient settings. VAL-083 combination with rucaparib produced synergistic cytotoxicity in the HR-deficient setting, while VAL-083 combination with veliparib was additive. These data demonstrate that VAL-083 can synergize with some PARPi in both HR-proficient and HR-deficient settings. CONCLUSION: Our results demonstrate a distinct DNA-damaging mechanism for VAL-083, resulting in the ability to overcome cisplatin-resistance in HR-impaired tumors. In addition, VAL-083 synergized with several PARPi, particularly olaparib, rucaparib and talazoparib, in both HR-proficient and deficient ovarian tumor cells.
Citation Format: Anne Steino, Guangan He, Beibei Zhai, Jeffrey Bacha, Dennis M. Brown, Mads Daugaard, Zahid H. Siddik. VAL-083 (dianhydrogalactitol) synergizes with PARP inhibitors in BRCA-proficient and BRCA-deficient ovarian cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P053.