title: Aflibercept and Ang1 supplementation improve neoadjuvant or adjuvant chemotherapy in a preclinical model of resectable breast cancer.
abstract: Phase III clinical trials evaluating bevacizumab (an antibody to the angiogenic ligand, VEGF-A) in breast cancer have found improved responses in the presurgical neoadjuvant setting but no benefits in the postsurgical adjuvant setting. The objective of this study was to evaluate alternative antiangiogenic therapies, which target multiple VEGF family members or differentially modulate the Angiopoietin/Tie2 pathway, in a mouse model of resectable triple-negative breast cancer (TNBC). Neoadjuvant therapy experiments involved treating established orthotopic xenografts of an aggressive metastatic variant of the MDA-MB-231 human TNBC cell line, LM2-4. Adjuvant therapies were given after primary tumor resections to treat postsurgical regrowths and distant metastases. Aflibercept ('VEGF Trap', which neutralizes VEGF-A, VEGF-B and PlGF) showed greater efficacy than nesvacumab (an anti-Ang2 antibody) as an add-on to neoadjuvant/adjuvant chemotherapy. Concurrent inhibition of Ang1 and Ang2 signaling (through an antagonistic anti-Tie2 antibody) was not more efficacious than selective Ang2 inhibition. In contrast, short-term perioperative BowAng1 (a recombinant Ang1 variant) improved the efficacy of adjuvant chemotherapy. In conclusion, concurrent VEGF pathway inhibition is more likely than Ang/Tie2 pathway inhibition (e.g., anti-Ang2, anti-Ang2/Ang1, anti-Tie2) to improve neoadjuvant/adjuvant chemotherapies for TNBC. Short-term perioperative Ang1 supplementation may also have therapeutic potential in conjunction with adjuvant chemotherapy for TNBC.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Florence T H
authors.initials: FT
authors.lastname: Wu
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Marta
authors.initials: M
authors.lastname: Paez-Ribes
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Elena
authors.initials: E
authors.lastname: Bogdanovic
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D042683:Angiopoietin-1 / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006801:Humans; D051379:Mice; D020360:Neoadjuvant Therapy; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor