Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer

Victoria L. Codony, Mahvash Tavassoli*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

33 Citations (Scopus)

Abstract

Most solid tumors, such as head and neck cancers, feature a hypoxic microenvironment due to angiogenic dysregulation and the consequent disruption of their vascular network. Such nutrient-deprived environment can induce genomic changes in several tumor cell populations, conferring survival and proliferative advantages to cancer cells through immunosuppression, metabolic switches and enhanced invasiveness. These transcriptional changes, together with the selective pressure hypoxia exerts on cancer cells, leads to the propagation of more aggressive and stress-resistant subpopulations increasing therapy resistance and worsening patient outcomes. Although extensive preclinical and clinical studies involving hypoxia-targeted drugs have been performed, most of these drugs have failed late-stage clinical trials and only a few have managed to be implemented in clinical practice. Here, we provide an overview of three main strategies to target tumor hypoxia: HIF-inhibitors, hypoxia-activated prodrugs and anti-angiogenic agents; summarizing the clinical advances that have been made over the last decade. Given that most hypoxia-targeted drugs seem to fail clinical trials because of insufficient drug delivery, combination with anti-angiogenic agents is proposed for the improvement of therapy response via vascular normalization and enhanced drug delivery. Furthermore, we suggest that using novel nanoparticle delivery strategies might further improve the selectivity and efficiency of hypoxia-targeted therapies and should therefore be taken into consideration for future therapeutic design. Lastly, recent findings point out the relevance that hypoxia-targeted therapy is likely to have in head and neck cancer as a chemo/radiotherapy sensitizer for treatment efficiency improvement.

Original languageEnglish
Article number101017
JournalTranslational Oncology
Volume14
Issue number3
DOIs
Publication statusPublished - Mar 2021

Keywords

  • Anti-angiogenic therapy
  • Head and neck cancer
  • HIF inhibitors
  • Hypoxia
  • Hypoxia-activated prodrugs
  • Nanoparticles
  • Therapy resistance

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