Background and Aim: Advanced pancreatic cancer is both deadly and difficult to treat with success. Here, we disseminate the results of comprehensive preclinical studies which laid a strong foundation for the rapid bench to bedside development of nab-paclitaxel, an albumin-bound formulation of paclitaxel, in combination with gemcitabine, a regimen recently approved by U.S. Food and Drug Administration as a first-line treatment for patients with metastatic pancreatic cancer.
Materials and Methods: We enrolled a total of 650 mice with established pancreatic tumors originated from a collection of patient-derived pancreatic cancer xenografts. The present study investigated the anti-tumor activity, survival advantage and mechanism of action of nab-paclitaxel or Cremophor EL™ (CreEL)-based paclitaxel monotherapy and in combination with gemcitabine.
Results: When tested in mice with subcutaneous tumors originating from 11 separate individual patient xenografts, nab-paclitaxel plus gemcitabine treatment demonstrated superior tumor regression response, robustly depleted the tumor desmoplatic stroma, leading to enhanced gemcitabine uptake (2.8-fold) in the tumor compared to tumors in the gemcitabine alone treated mice. In orthotopic models, nab-paclitaxel treatment leads to an average of 3.64-fold decrease in primary tumor volumes compared to CreEL-based paclitaxel. Intra-tumor stromal collapse combined with decreased tumor cell proliferation was clearly evident in the primary tumors of nab-paclitaxel treated mice compared to CreEL-based paclitaxel, when the mice were sacrificed immediately after five consecutive day's treatment or three weeks after the final dose of the agents. In a highly aggressive orthotopic model, nab-paclitaxel plus gemcitabine treatment prevented primary tumor progression, and metastatic spread to liver, lymph nodes and diaphragm. While CreEL-based paclitaxel plus gemcitabine treatment failed to enhance mouse survival compared to gemcitabine monotherapy, the nab-paclitaxel plus gemcitabine combination proved statistically significant (p=0.0133) in enhancing survival. nab-paclitaxel monotherapy demonstrated statistically significant survival advantage compared to CreEL-based paclitaxel monotherapy (p=0.0072). Remarkably, nab-paclitaxel monotherapy was equivalent to nab-paclitaxel plus gemcitabine in providing survival advantage in a highly aggressive metastatic model of pancreatic cancer.
Conclusion: Our results demonstrated that co-treatment with nab-paclitaxel and gemcitabine resulted in superior tumor regression response, stromal depletion and enhanced intra-tumoral gemcitabine uptake compared with either single agent alone. nab-paclitaxel demonstrated superior anti-tumor activity and provided a statistically significant survival advantage compared to CreEL-based paclitaxel. Our results provide further rationale for future preclinical and clinical trials in pancreatic cancer using nab-paclitaxel as a backbone therapy in combination with novel experimental and targeted agents.
Acknowledgements: The study was supported by funding from Celgene Corporation and AACR-Stand Up To Cancer Dream Team Translational Cancer Research Grant (SU2C-AACR-DT0509).
Citation Format: N.V Rajeshkumar, Shinichi Yabuuchi, Shweta G. Pai, Scott Bateman, Ellen Filvaroff, Daniel W. Pierce, Carla Heise, Daniel D. Von Hoff, Anirban Maitra, Manuel Hidalgo. Highlights of innovative preclinical studies which guided the rapid bench to bedside development of nab-paclitaxel plus gemcitabine combination for the treatment of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-94. doi:10.1158/1538-7445.AM2014-LB-94