title: Hypoxia-activated prodrugs: paths forward in the era of personalised medicine.
abstract: Tumour hypoxia has been pursued as a cancer drug target for over 30 years, most notably using bioreductive (hypoxia-activated) prodrugs that target antineoplastic agents to low-oxygen tumour compartments. Despite compelling evidence linking hypoxia with treatment resistance and adverse prognosis, a number of such prodrugs have recently failed to demonstrate efficacy in pivotal clinical trials; an outcome that demands reflection on the discovery and development of these compounds. In this review, we discuss a clear disconnect between the pathobiology of tumour hypoxia, the pharmacology of hypoxia-activated prodrugs and the manner in which they have been taken into clinical development. Hypoxia-activated prodrugs have been evaluated in the manner of broad-spectrum cytotoxic agents, yet a growing body of evidence suggests that their activity is likely to be dependent on the coincidence of tumour hypoxia, expression of specific prodrug-activating reductases and intrinsic sensitivity of malignant clones to the cytotoxic effector. Hypoxia itself is highly variable between and within individual tumours and is not treatment-limiting in all cancer subtypes. Defining predictive biomarkers for hypoxia-activated prodrugs and overcoming the technical challenges of assaying them in clinical settings will be essential to deploying these agents in the era of personalised cancer medicine.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Francis W
authors.initials: FW
authors.lastname: Hunter
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, ON M5S 1A1, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A1, Canada.
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015687:Cell Hypoxia; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D057285:Precision Medicine; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D010088:Oxidoreductases