title: Multimodal targeting of tumor vasculature and cancer stem-like cells in sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy.
abstract: Vascular endothelial growth factor A (VEGF-A) inhibition with pazopanib is an approved therapy for sarcomas, but likely results in compensatory pathways such as upregulation of hypoxia inducible factor 1α (HIF-1α). In addition, cancer stem-like cells can preferentially reside in hypoxic regions of tumors and be resistant to standard chemotherapies. In this study, we hypothesized that the combination of VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy with evofosfamide would be an effective multimodal strategy. Multimodal therapy was examined in one genetically engineered and two xenograft mouse models of sarcoma. In all three models, multimodal therapy showed greater efficacy than any single agent therapy or bimodality therapy in blocking tumor growth. Even after cessation of therapy, tumors treated with multimodal therapy remained relatively dormant for up to 2 months. Compared to the next best bimodality therapy, multimodal therapy caused 2.8-3.3 fold more DNA damage, 1.5-2.7 fold more overall apoptosis, and 2.3-3.6 fold more endothelial cell-specific apoptosis. Multimodal therapy also decreased microvessel density and HIF-1α activity by 85-90% and 79-89%, respectively, compared to controls. Sarcomas treated with multimodal therapy had 95-96% depletion of CD133(+) cancer stem-like ells compared to control tumors. Sarcoma cells grown as spheroids to enrich for CD133(+) cancer stem-like cells were more sensitive than monolayer cells to multimodal therapy in terms of DNA damage and apoptosis, especially under hypoxic conditions. Thus multimodal therapy of sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy effectively blocks sarcoma growth through inhibition of tumor vasculature and cancer stem-like cells.
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Changhwan
authors.initials: C
authors.lastname: Yoon
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Chang
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.affiliation: Threshold Pharmaceuticals, South San Francisco, CA, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Sam S
authors.initials: SS
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D034622:RNA Interference; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: chemotherapy; hypoxia; hypoxia inducible factor 1α; sarcomas; vascular endothelial growth factor A