Abstract 4681: Oseltamivir phosphate completely ablates tumor refractoriness to conventional chemotherapeutics abraxane and gemcitabine in xenografts of tumors in mouse model of human pancreatic cancer

Abstract

Abstract Pancreatic cancer, the fourth leading cause of cancer-related death worldwide, is highly aggressive and associated with a poor prognosis. Resistance to drug therapy, along with high rates of metastasis, contributes to the low survival rates in patients diagnosed with pancreatic cancer. Gemcitabine, a chemotherapeutic agent, is the current standard of care for patients with the disease. Although gemcitabine has higher success rates than any other chemotherapeutic in use, patients receiving gemcitabine still only have progression-free survival in the range of 0.9-4.2 months. Given the poor response rate to gemcitabine, pancreatic cancer cells develop rapid resistance to this drug. Here, we investigated the proof of concept for a reported entirely new anticancer drug, oseltamivir phosphate (OP), to overcome tumor refractoriness to gemcitabine and abraxane in heterotopic xenografts of pancreatic MiaPaCa-2 tumors growing in RAGxCγ double mutant mice. The data clearly indicate that mice treated with 50mg/kg abraxane alone (1x weekly, i.p.) at Day 33 post implantation slightly restrained tumor growth until Day70 at which time the tumor developed resistance to abraxane and rapidly increased in tumor volume and spread to the lungs. In contrast, abraxane in combination with OP 20mg/kg (3x weekly, i.p.) abrogated the tumor resistance to abraxane and impeded tumor growth and metastatic spread to the lung. Very interestingly, with comparable results to abraxane/OP, mice treated with 30mg/kg gemcitabine (1x weekly, i.p.) at Day31 post implantation developed tumor resistance at Day50 to gemcitabine and rapidly increased in tumor volume and spread to the lung. Gemcitabine in combination with 20mg/kg OP (3x weekly, i.p.) completely impeded the tumor growth, chemoresistance and spread to the lungs with long term survival at Day 240 with no relapse and metastasis. The significance of these findings is the first to show that OP in combination with standard, clinical chemotherapeutics can impede (a) human pancreatic tumor growth, (b) tumor neovascularization, (c) liver and lung metastases, and (d) tumor refractoriness to conventional chemotherapeutics, as well (e) significantly extending survival rates with no relapse and metastasis. Citation Format: Myron R. Szewczuk. Oseltamivir phosphate completely ablates tumor refractoriness to conventional chemotherapeutics abraxane and gemcitabine in xenografts of tumors in mouse model of human pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4681.