Abstract B207: Darinaparsin is an anti-solid tumor cytotoxin in vivo.

Abstract

Abstract Background: Darinaparsin (DPS; provided by ZIOPHARM Oncology, Inc.) is a novel organic arsenical with promising anticancer activity and a favorable systemic toxicity profile. Compared to the inorganic arsenical anti-cancer drug, arsenic trioxide (ATO), DPS has higher in vitro potency against solid tumor cells under both normoxic (NO) and hypoxic (HO) conditions. Under HO, an important feature of the solid tumor microenvironment, DPS activity was not dependent on the generation of reactive oxygen species and subsequent oxidative stress. Here we report results of studies of the in vivo anti-tumor effect of DPS in xenograft solid tumor models and patient-derived prostate cancer tumor grafts, as well as mechanistic studies including cDNA microarray and other experiments to study mechanisms of action of DPS. Materials and Methods: To test the in vivo efficacy of DPS, we used mouse models of human prostatic [hormone-independent (HI) LAPC-4] and pancreatic [PANC-1] xenograft tumors implanted subcutaneously in immunodeficient mice. In addition, patient-derived prostate cancer tissues were precision-cut and implanted as tissue slice grafts (TSGs) under the renal capsule in immunodeficient mice. Both tumor models were treated with DPS (100 mg/kg, IP, 3 times/wk × 4 wks), or saline as a control. The TSG tumor growth was assessed by immunohistochemistry (AMACR/p63) staining, and the results were represented as the total tumor area in TSG sections. The effects of DPS on JNK and HIF1 signaling pathways were determined by western blot and RT-qPCR. Using cDNA microarray and subsequent pathway analyses, we studied the effect of DPS and ATO on global gene expression in HI-LAPC-4 cells. Normal and transformed Mouse Embryonic Fibroblasts (MEFs) overexpressing the oncogene HRAS and E1A were used to study the effect of DPS on these oncogenes that are important for susceptibility to cell killing. Results: In both HI-LAPC-4 and PANC-1 tumor models, DPS significantly inhibited tumor growth (P < 0.0001). The average tumor volume doubling time increased from 3.95 days (95% CI: 4.22 − 3.72) to 11.8 days (95% CI: 11.2 − 12.5) in HI-LAPC-4 tumors (P < 0.001), and 3.83 days (95% CI: 3.65 − 4.02) to 6.82 (95% CI: 6.59 − 7.07) in PANC-1 tumors (P < 0.001). In the TSG model, DPS decreased the tumor growth by 50% in 4 of the 6 TSGs as compared with the paired control (P = 0.139). DPS-treated mice exhibited decreased physical activity and early body weight loss (∼5–10% in the 1st wk), but no other significant systemic toxicities as assessed by organ histology and blood biochemistry. As previously reported in leukemia cells, JNK was activated by DPS under both NO and HO; however, the JNK inhibitor SP600125 did not inhibit DPS activity. HIF1α, a major regulator of cell survival under HO, was not affected by DPS. Microarray analysis revealed a significant effect of DPS (but not ATO) on RAS and MYC oncogenic pathways. Compared to normal MEFs, oncogene (RAS/E1A) transformed MEFs were markedly more sensitive to DPS-induced apoptosis under both NO and HO. Conclusions: DPS had significant cytotoxic activity in vivo in the two tumor models studied (HI-LAPC-4 and PANC-1) in mice at a dose that was well-tolerated. This may be due, in part, to DPS inhibition of mutant and dysregulated oncogenic pathways that are required for survival of tumor, but not normal cells. Since DPS is in early clinical development as a single agent, these findings may have near term translational potential. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B207.