Abstract 1763: Arsenoplatin-7, a family member of arsenoplatins, as a novel therapeutic strategy to overcome platinum-resistance in ovarian cancer
Authors: Wenan Qiang, Denana Miodragovic, Yi Yang, Bong Jin Hong, Chi-Hao Luan, David Fang, Daniela E. Matei, Thomas V. O’Halloran
Journal: Cancer Research (2025)

Abstract Ovarian cancer (OC) is the fifth leading cause of cancer death in women. OC inevitably acquires resistance to platinum-based chemotherapy, leading to treatment failure and disease progression. There is an unmet need to overcome platinum OC resistance. Arsenic trioxide (ATO) is an approved drug for treating acute promyelocytic leukemia, but not in solid tumors. Arsenoplatins (APs), a family of novel anticancer dual-pharmacophore agents containing ATO in the form of arsenous acid attached to a platinum center, can deliver ATO into the tumor cells. APs have previously shown in vitro potency in leukemia, breast, and ovarian cell lines in NCI-60 screens. It was hypothesized that APs (AP-1 and AP-7) could have therapeutic effects in cisplatin (CDDP) resistant OC due to the unique nature of the drug delivery. Three paired CDDP-sensitive and resistant OC cell lines (A2780, SKOV3, and OVCAR5) were used to test the potency of AP-1 and AP-7 compared to CDDP, ATO, or a combination of both. In addition, a single dose of maximum tolerated dose (MTD) was determined in mice, and the efficacy of AP-1 and AP-7 was evaluated in clinically translational platinum-resistant OC PDX tumor models. RNA-seq analysis of tumor tissue and in silico molecular docking was further studied to explore the mechanism of action to identify potential biomarkers for AP-7 therapy. AP-1 and AP-7 demonstrated great potency and showed similar cell growth inhibition in all tested CDDP-resistant cell lines. AUC, a parameter of combined measurement of both Emax and IC50, was used to rank the effectiveness of APs in these cell lines, with ATO being the most potent, followed by a combination of ATO and CDDP, then AP-1, AP-7, and CDDP was the least potent. Compared to the MTD for CDDP and ATO in mice, APs have much lower toxicity(higher MTD). AP-7, but not AP-1, demonstrated efficacy in the platinum-resistant OC PDX tumor study. AP-7 showed significant tumor volume reduction starting from week 3 (P&amp;lt;0.01); at the end of 5 weeks, there was a significant reduction of 60.78% (P&amp;lt;0.001) in tumor volume and 42.80% (P&amp;lt;0.01) in tumor weight over control. No body weight change was observed throughout the study. Molecular docking of AP-7 with GLI1 revealed that AP-7 binds to a pocket in proximity to the Zn-binding site of GLI1, potentially disrupting Zn coordination by interacting with key cysteine and histidine residues. The RNA-seq sequencing from AP-7 treated PDX tumor tissues was completed, and data analysis is ongoing for differential gene expressions and alternative splicing. Our preliminary results indicate that AP-7 is a potential therapeutic agent for overcoming platinum resistance in OC by delivering arsenous acid to tumor cells with greater efficacy and less toxicity. However, the prediction of potential target GLI1 warrants further validation. Citation Format: Wenan Qiang, Denana Miodragovic, Yi Yang, Bong Jin Hong, Chi-Hao Luan, David Fang, Daniela E. Matei, Thomas V. O’Halloran. Arsenoplatin-7, a family member of arsenoplatins, as a novel therapeutic strategy to overcome platinum-resistance in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1763.