Synergy of nab-paclitaxel and bevacizumab in eradicating large orthotopic breast tumors and preexisting metastases. Neoplasia 2011 Apr;13(4):327-38
Date
04/08/2011Pubmed ID
21472137Pubmed Central ID
PMC3071081DOI
10.1593/neo.101490Scopus ID
2-s2.0-79953682278 (requires institutional sign-in at Scopus site) 68 CitationsAbstract
INTRODUCTION: Patients with metastatic disease are considered incurable. We previously showed that nabpaclitaxel (nanoparticle albumin-embedded paclitaxel) combined with anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, eradicates orthotopic small-sized breast tumors and metastasis. Here, we assessed this therapy in two models of advanced (450-600 mm(3)) breast tumors and delineated VEGF-A-dependent mechanisms of tumor resistance.
METHODS: Mice with luciferase-tagged advanced MDA-MB-231 and MDA-MB-435 tumors were treated with saline, nab-paclitaxel (10 or 30 mg/kg), bevacizumab (4 mg/kg), or combined drugs. Lymphatic and lung metastases were measured by luciferase assay. Proinflammatory and survival pathways were measured by ELISA, Western blot and immunohistochemistry.
RESULTS: Nab-paclitaxel transiently suppressed primary tumors by 70% to 90% but had no effect on metastasis. Coadministration of bevacizumab increased the response rate to 99%, including 71% of complete responses in MDA-MB-231-bearing mice treated concurrently with 30 mg/kg of nab-paclitaxel. This combinatory regimen significantly reduced or eliminated preexisting lymphatic and distant metastases in MDA-MB-231 and MDA-MB-435 models. The mechanism involves paclitaxel-induced NF-κB pathway that upregulates VEGF-A and other tumor prosurvival proteins.
CONCLUSIONS: Bevacizumab prevents tumor recurrence and metastasis promoted by nab-paclitaxel activation of NF-κB pathway. Combination therapy with high-dosed nab-paclitaxel demonstrates the potential to eradicate advanced primary tumors and preexisting metastases. These findings strongly support translating this regimen into clinics.
Author List
Volk LD, Flister MJ, Chihade D, Desai N, Trieu V, Ran SMESH terms used to index this publication - Major topics in bold
AlbuminsAnimals
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols
Bevacizumab
Breast Neoplasms
Cell Line, Tumor
Disease Progression
Drug Synergism
Female
Humans
Mice
Mice, SCID
Neoplasm Metastasis
Neoplasm Staging
Neoplasm Transplantation
Paclitaxel
Transplantation, Heterotopic
Xenograft Model Antitumor Assays
