Journal Article

Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer

Hou, Shihe, Pierce, Daniel W, Yabuuchi, Shinichi, Tong, Zeen, Hidalgo, Manuel, Heise, Carla, Maitra, Anirban, Rajeshkumar, N V, Von Hoff, Daniel D, Pai, Shweta G, Bateman, Scott

2016

Overview

Background: Albumin-bound paclitaxel ( nab -paclitaxel, nab- PTX) plus gemcitabine (GEM) combination has demonstrated efficient antitumour activity and statistically significant overall survival of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) compared with GEM monotherapy. This regimen is currently approved as a standard of care treatment option for patients with metastatic PDAC. It is unclear whether cremophor-based PTX combined with GEM provide a similar level of therapeutic efficacy in PDAC. Methods: We comprehensively explored the antitumour efficacy, effect on metastatic dissemination, tumour stroma and survival advantage following GEM, PTX and nab- PTX as monotherapy or in combination with GEM in a locally advanced, and a highly metastatic orthotopic model of human PDAC. Results: Nab- PTX treatment resulted in significantly higher paclitaxel tumour plasma ratio (1.98-fold), robust stromal depletion, antitumour efficacy (3.79-fold) and survival benefit compared with PTX treatment. PTX plus GEM treatment showed no survival gain over GEM monotherapy. However, nab- PTX in combination with GEM decreased primary tumour burden, metastatic dissemination and significantly increased median survival of animals compared with either agents alone. These therapeutic effects were accompanied by depletion of dense fibrotic tumour stroma and decreased proliferation of carcinoma cells. Notably, nab- PTX monotherapy was equivalent to nab- PTX plus GEM in providing survival advantage to mice in a highly aggressive metastatic PDAC model, indicating that nab- PTX could potentially stop the progression of late-stage pancreatic cancer. Conclusions: Our data confirmed that therapeutic efficacy of PTX and nab -PTX vary widely, and the contention that these agents elicit similar antitumour response was not supported. The addition of PTX to GEM showed no survival advantage, concluding that a clinical combination of PTX and GEM may unlikely to provide significant survival advantage over GEM monotherapy and may not be a viable alternative to the current standard-of-care nab -PTX plus GEM regimen for the treatment of PDAC patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/1647/767/70 / 692/699/67/1059/99 / 692/699/67/1504/1713 / 692/700/565/1436/1437 / Albumins - administration & dosage / Animals / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinoma, Pancreatic Ductal - drug therapy / Carcinoma, Pancreatic Ductal - secondary / Cell Proliferation / Deoxycytidine - administration & dosage / Deoxycytidine - analogs & derivatives / Drug Resistance / Epidemiology / Humans / Kidney Neoplasms - drug therapy / Kidney Neoplasms - secondary / Liver Neoplasms - drug therapy / Liver Neoplasms - secondary / Lung Neoplasms - drug therapy / Lung Neoplasms - secondary / Male / Mice / Mice, Nude / Molecular Medicine / Neoplasm Metastasis / Neovascularization, Pathologic / Oncology / Paclitaxel - administration & dosage / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - pathology / Polyethylene Glycols - administration & dosage / Splenic Neoplasms - drug therapy / Splenic Neoplasms - secondary / Translational Therapeutics / Xenograft Model Antitumor Assays