Abstract C246: nab®-paclitaxel targets tumor stroma and results, combined with gemcitabine, in high efficacy against pancreatic cancer models

Abstract

Abstract nab®-paclitaxel (Abraxane ™, Abraxis Bioscience, Los Angeles, CA) is an albumin-bound nano particle formulation of paclitaxel that may target SPARC (secreted protein acid-rich in cysteine). In a phase I/II study in patients with advanced pancreatic cancer, the combination of nab®-paclitaxel and gemcitabine resulted in impressive clinical activity with an objective response rate of 40%, 10.3 months median survival and 78 % of patients having a decrement of CA199 > 50 % (Von Hoff et al, ASCO 2009). To gain insight into the mechanisms underlying the high efficacy of this combination, we treated 11 freshly generated pancreatic cancer xenografts from the Johns Hopkins PancXenoBank collection. nab®-paclitaxel, in combination with gemcitabine, doubled the response rate of either agent alone and resulted in a 57% response rate, mimicking the results obtained in the clinical trial. Tumors treated with nab®-paclitaxel showed a marked decrement in the otherwise abundant fibrotic stroma characteristic of pancreatic cancer and present in control and gemcitabine only treated animals. The elimination of the stroma resulted in marked cellular tumors and increased tumor vascularization and cell-vessel proximity. Consequently, the intratumoral concentration of gemcitabine increased by 3.7 fold in mice treated with nabR-paclitaxel and gemcitabine versus those receiving gemcitabine alone. We conclude that nab®-paclitaxel effectively eliminates pancreatic cancer stroma resulting in increased delivery of gemcitabine and high antitumor effects. Targeting tumor stroma appears a promising strategy in pancreatic cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C246.