Abstract 686: Treatment of pancreatic carcinoma by Cytotech Labs API 31510

Abstract

Abstract Pancreatic Carcinoma (PC) is one of the deadliest cancers most clinically difficult to manage since diagnoses usually occur in late-stage disease. In early PC, resection is possible; however in most patients advanced disease mitigates the feasibility of resection. All chemotherapeutic regimens are ineffective for patients, with best outcome usually only palliative. In this regard, we have developed a novel intravenous formulation, API 31510, which induces apoptosis of a pancreatic carcinoma cell line, MIA-PaCa-2 in vitro. We therefore proceeded to test this formula in immunocompromised animals injected with 10×106MIA-Paca2 cells. For these experiments, immunocompromised animals were injected with MIA-PaCa2 suspended in matrigel. 2 weeks after transplantation with MIA Paca2, API 31510 and vehicle controls were administered 3 times/week for 4 weeks with surviving animals sacrificed at day 60. Animals were randomized into 8 groups of 30 rats each; group 1 (no treatment), group 2 (saline), group 3 (vehicle), group 4 (0.5 mg/kg API 31510), group 5 (5 mg/kg API 31510), group 6 (10 mg/kg API 31510), group 7 (25 mg/kg API 31510), and group 8 (50 mg/kg API 31510). In groups 1, 2 and 3 deaths were recorded 21 days after the injection of MIA-PaCa-2. In contrast, all other groups showed significant dose-dependent increase in survival times. Group 8 had 60% of animals alive with only 4 animals exhibiting visible tumors at day 60. In separate experiments, we explored whether API 31510 protects from doxorubicin toxicity. To this effect, we treated rats with doxorubicin (35 mg/kg) and then injected API 31510 in one group. Those who were not treated, died on days 6-11, whereas those treated with API 31510 were protected against doxorubicin toxicity. To assess the mechanism of action of Cytotech API 31510 in Mia-Paca2, a combination of transcriptomic, proteomic and metabolic analysis was employed. Mia-Paca2 cells exhibit the Warburg effect characterized by high glycolytic flux and extracellular acidification rates (ECAR) that is reversed in the presence of API 31510. Exposure to API 31510 induces a change in the gene expression profiling of intrinsic apoptotic factors and proteomic analysis using DAVID show increase in components regulating protein expression, processing and cytoskeletal remodeling with concomitant decrease in components regulating nuclear metabolic processes and chromatin function. The ability of Cytotech API 31510 to induce global changes in cellular transcriptomic and proteomic functions along induction of programmed cell death in association with shift in mitochondrial energy utilization pathways represents a unique mechanism targeting pathways within the spectrum of Warburg Phenomenon for therapy of pancreatic cancer. Taken together, these findings suggest that API 31510 may offer a new approach to treatment and management of pancreatic cancer, while mitigating dose-limiting toxicities in other chemotherapeutic interventions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 686. doi:10.1158/1538-7445.AM2011-686