Abstract A159: Dianhydrogalactitol (VAL-083) enhances activity of platinum drugs in non-small cell lung cancer

Abstract

Abstract Non-small cell lung cancer (NSCLC) is treated with surgery followed by chemotherapy with either tyrosine kinase inhibitors (TKIs) or platinum-based regimens, but long term prognosis is poor. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent with proven activity against NSCLC in preclinical and clinical studies. VAL-083 is approved for the treatment of lung cancer in the Peoples Republic of China (PRC, Approval No. Guayo Zhunzi H45021133); however, clinical use has been limited by lack of mechanistic data. Here we aimed to investigate in vitro i) the role of p53 status in VAL-083 activity, ii) VAL-083 cytotoxicity in a panel of NSCLC cell lines, iii) the combination of VAL-083 with cisplatin or oxaliplatin in NSCLC cells. We further studied the combination of VAL-083 with cisplatin in NSCLC in vivo. Dependence on p53 status was investigated in isogenic HCT-116p53-/- and HCT-116p53+/+ models. VAL-083, cisplatin and oxaliplatin cytotoxicity was tested in a panel of 9 human NSCLC cell lines: 4 wt, 4 mutant and 1 null for p53. The combination potential for VAL-083 with cisplatin or oxaliplatin was investigated in 3 human NSCLC cell lines; H460 (p53wt), A549 (p53wt) and H1975 (p53mut) by determining superadditivity and synergy using the criteria of combination index (CI)<1. Cytotoxicity was monitored on day 5 with the MTT assay. The in vivo activity of VAL-083 (2, 2.5, or 3 mg/kg i.p.) in combination with cisplatin (2 mg/kg i.v.) was tested in Rag2 mice bearing A549 xenograft tumors. Studies in HCT-116 models showed that loss of p53 increased resistance to cisplatin and oxaliplatin by 3- and 6-fold, respectively, while resistance to VAL-083 was <2-fold, suggesting a more p53-independent mechanism for VAL-083. As single agents, VAL-083, cisplatin and oxaliplatin showed good cytotoxicity in all NSCLC cell lines, with TKI-resistant cell line H460 as the most sensitive (IC50 < 0.5 uM). The combination of VAL-083 with cisplatin or oxaliplatin in H460, A549 and H1975 cells demonstrated significant super-additivity (p<0.05) and synergism (CI < 1) for both combinations in all 3 cell lines. This strongly favors non-overlapping mode of action between the platinum drugs and VAL-083 and demonstrates synergism in TKI-resistant cell lines. In the in vivo model, tumor growth delays of 11, 18 and 25 days were observed for cisplatin combined with 2, 2.5 or 3 mg/kg VAL-083, respectively, while no tumour growth delay was seen between untreated and cisplatin. The median survival time was increased by 2 days for cisplatin alone, while VAL-083 (2, 2.5 and 3 mg/kg) combined with cisplatin increased survival by 17, 17, and 14 days, respectively. In conclusion, when combined with cisplatin or oxaliplatin, VAL-083 demonstrates superadditivity/synergy against NSCLC cells, independent of their p53 status. Further, VAL-083 in combination with cisplatin significantly increased median survival in vivo. These results strongly suggest a potential for VAL-083 as part of combination treatment with platinum drugs for NSCLC, including drug-resistant phenotypes. A clinical trial is planned under the context of the existing PRC approval to investigate these observations in a clinical setting. Results, if favorable, will support expanded clinical use of VAL-083 in PRC and will serve as the basis for global development of VAL-083 as a potentially important chemotherapeutic agent in the treatment of NSCLC. Citation Format: Anne Steino, Jeffrey A. Bacha, Guanghan He, Sarath Kanekal, Nancy Dos Santos, Shun Lu, Dennis M. Brown, Zahid H. Siddik. Dianhydrogalactitol (VAL-083) enhances activity of platinum drugs in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A159.