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

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.

Keywords: Anti-angiogenic therapy; HIF inhibitors; Head and neck cancer; Hypoxia; Hypoxia-activated prodrugs; Nanoparticles; Therapy resistance.

Graphical abstract

Fig. 1

Hypoxia signalling pathway: (A) Under normoxic conditions HIF-α is hydroxylated by prolyl hydroxylase domain proteins (PHDs), allowing the interaction between HIF-α and the von Hippel-Lindau protein (pVHL). Consequently, pVHL will recruit an E3 ubiquitin ligase complex that will target HIF-α for proteasomal degradation. (B) Under hypoxic conditions however, the hydroxylation reaction does not take place and HIF-α is now free to translocate into the nucleus and associate with HIF-1β and coactivator p300/CBP, forming a heterodimeric transcription complex. Binding of this HIF-α/β complex to hypoxia response elements (HREs) will result in the upregulation of HIF target genes, regulating various cellular processes such as angiogenesis (VEGF and ANG-1/2), invasiveness (Vimentin), metabolism (CA9 and GLUT-1/3) and immunity (TGF-β and PD-L1).

Fig. 2

Anti-angiogenic drugs for vascular normalization: (A) The tumor-released pro-angiogenic factors disrupt the angiogenic homeostasis and lead to an aberrant and impaired vasculature which is not able to properly deliver oxygen to the cells, causing perfusion-limited hypoxia. (B) Anti-angiogenic drugs (AAs) given at low doses are able to revert the aberrant neovascularization and normalize the vasculature, re-perfusing tumor cells. (C) Anti-angiogenic drugs given at high doses destroy the vascular network and leave tumor cells without nearby vessels, causing diffusion-limited hypoxia. Figure inspired by Meaney et al., 2020.

Fig. 3

Hypoxia-activated prodrugs: (A) Under normoxic conditions hypoxia-activated prodrugs undergo 1 or 2 electron reductions performed by endogenous oxidoreductases, which can be immediately reversed by available oxygen inactivating the drug. (B) Under hypoxic conditions however, reduction of hypoxia-activated prodrugs cannot be reversed due to the lack of available oxygen, leading to the stabilization of cytotoxic metabolites which normally induce cell death through DNA damage or inhibition of tyrosine kinase receptors.

Fig. 4

Nanoparticles combining AAs (COMB) + HAPs (TH-302): (A) Initial release of the anti-angiogenic COMB reverses neovascularization, normalizing tumor vasculature thus allowing efficient delivery of nanoparticles containing TH-302. (B) Delayed release of the hypoxia-activated prodrug TH-302 allows to trap it in the required hypoxic tumor environment, where its activity will be enhanced by low oxygen concentration.