title: Synergy of nab-paclitaxel and bevacizumab in eradicating large orthotopic breast tumors and preexisting metastases.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Volk
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Flister
authors.forename: Deena
authors.initials: D
authors.lastname: Chihade
authors.forename: Neil
authors.initials: N
authors.lastname: Desai
authors.forename: Vuong
authors.initials: V
authors.lastname: Trieu
authors.forename: Sophia
authors.initials: S
authors.lastname: Ran
mesh_terms: D000418:Albumins / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D016042:Transplantation, Heterotopic; D023041:Xenograft Model Antitumor Assays
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D017239:Paclitaxel