title: Resistance to metronomic chemotherapy and ways to overcome it.
abstract: Therapeutic resistance is amongst the major determinants of cancer mortality. Contrary to initial expectations, antivascular therapies are equally prone to inherent or acquired resistance as other cancer treatment modalities. However, studies into resistance to vascular endothelial growth factor pathway inhibitors revealed distinct mechanisms of resistance compared to conventional cytotoxic therapy. While some of these novel mechanisms of resistance also appear to be functional regarding metronomic chemotherapy, herein we summarize available evidence for mechanisms of resistance specifically described in the context of metronomic chemotherapy. Numerous preclinically identified molecular targets and pathways represent promising avenues to overcome resistance and enhance the benefits achieved with metronomic chemotherapy eventually. However, there are considerable challenges to clinically translate the preclinical findings.
authors.affiliation: Division of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Riesco-Martinez
authors.affiliation: Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: Parra
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.
authors.forename: Ronak
authors.initials: R
authors.lastname: Saluja
authors.affiliation: Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Francia
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; Division of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada. Electronic address: urban.emmenegger@sunnybrook.ca.
authors.forename: Urban
authors.initials: U
authors.lastname: Emmenegger
mesh_terms: D059250:Administration, Metronomic; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors
keywords: Antivascular tumor therapy; Chemoresistance; Metronomic chemotherapy; Therapeutic resistance