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Targeting hypoxia in cancer therapy

Key Points

  • Hypoxia represents a compelling therapeutic target, given that it has a major role in tumour development and resistance to therapy, and that the levels of hypoxia are more severe in most tumours than normal tissues.

  • One approach to targeting hypoxia seeks to develop bioreductive prodrugs that are activated by enzymatic reduction in hypoxic tissue. These prodrugs are chemically diverse and represent two distinct strategies: activation under moderate hypoxia (as exemplified by tirapazamine) or only under severe hypoxia (as exemplified by PR-104). In the latter case, diffusion of the active drug to less hypoxic cells is essential.

  • A second approach seeks small molecule inhibitors against molecular targets involved in the survival of hypoxic cells. Current interest focuses on the inhibition of the hypoxia-inducible factor 1 (HIF1), the unfolded protein response (UPR) and mTOR pathways, but the most important vulnerabilities in hypoxic cells are not well defined. Most molecularly targeted agents have been 'repurposed' from other applications, and have low selectivity as hypoxic cytotoxins.

  • Both approaches face substantial challenges in relation to off-target effects, which, ironically, also present opportunities. For bioreductive prodrugs, activation by aerobic reductases can contribute to normal tissue toxicity, but this is exploitable in tumours that highly express these enzymes. For molecularly targeted agents, hypoxia-independent signalling through the same pathways may provide opportunities for additional antitumour activity.

  • Both bioreductive prodrugs and molecularly targeted agents also need to overcome the problem of drug penetration through poorly perfused hypoxic tissue; strategies for addressing this requirement are being developed.

  • The current generation of bioreductive prodrugs generate DNA-reactive cytotoxins, making them difficult to combine with conventional chemotherapy because of overlapping toxicity. This challenge is stimulating the development of bioreductive prodrugs that release molecularly targeted agents as their effectors, potentially combining the best features of both approaches.

  • Given the marked heterogeneity in hypoxia between tumours of the same type, the clinical exploitation of hypoxia using all of these approaches will require their co-development with companion diagnostics for hypoxia (and for other determinants of sensitivity).

Abstract

Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population. It is a negative prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism and genomic instability. Given its central role in tumour progression and resistance to therapy, tumour hypoxia might well be considered the best validated target that has yet to be exploited in oncology. However, despite an explosion of information on hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumour hypoxia is to be realized. Here, we review the two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting hypoxia.

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Figure 1: Oxygen dependence of hypoxia-responsive processes in tumours.
Figure 2: Mechanisms of metabolic activation of bioreductive prodrugs.
Figure 3: Structures of bioreductive prodrugs.
Figure 4: Potential molecular targets for killing hypoxic cells in the oxygen-responsive signalling pathways that mediate adaptation to hypoxia.

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Acknowledgements

We thank our collaborators (R. Anderson, W. Denny, K. Hicks, C. Guise, A. Patterson, F. Pruijn, J. Smaill, M. Tercel and J. Wang) for many fruitful discussions that have helped to inform the views expressed here. The authors acknowledge financial support from the Health Research Council of New Zealand (W.R.W.) and the Maurice Wilkins Centre for Biodiscovery (M.P.H.).

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Mechanisms of resistance (and sensitivity) of hypoxic cells to cytotoxic therapy (PDF 428 kb)

Glossary

Bioreductive prodrugs

Biologically inactive molecules that are converted to an active drug by enzymatic reduction.

Superoxide

A free radical formed by a one-electron reduction of oxygen, including by electron transfer from a prodrug free radical. Despite its name, superoxide itself is not highly reactive and is generally less toxic than the reduced prodrug, so its generation represents a detoxification mechanism in aerobic cells.

Replication fork

The branch-point structure that forms between two DNA template strands during DNA replication at which nascent DNA synthesis is ongoing.

Homologous recombination

(HR). High-fidelity repair of DNA lesions, including double-strand breaks, in S and G2 phases of the cell cycle, using a sister chromatid as a template.

Multicellular spheroids

Spherical clusters of cells that grow large enough to become diffusion-limited, and thus model some features of the tumour microenvironment.

Multicellular layers

(MCLs). Three-dimensional cell cultures that model the extravascular compartment of tumours. Grown on collagen-coated micro-porous membranes, they allow measurement of drug diffusion and metabolism in tumour-like tissue.

Bystander effect

In the context of bioreductive prodrugs, the killing of adjacent cells that lack prodrug-activating ability through local diffusion of the active drug.

Pseudo-hypoxia

The induction of molecular responses analogous to those caused by hypoxia but triggered by other conditions.

Cap-dependent translation

Translation initiated by binding of the eIF4F complex to the methyl-7-G(5′)pppN structure (cap) at the 5′ end of the mRNA.

Synthetic lethal interaction

In genetics, an interaction between two non-lethal mutations that, in combination, confer lethality. In chemical genetics, this term can refer to interaction between a drug and mutation that confers greater drug-sensitivity than with the wild type.

Autochthonous tumours

Tumours that arise in the host being studied, as distinct from tumours introduced by transplantation.

Network medicine

Analysis of biological networks to derive understanding of disease and therapy.

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Wilson, W., Hay, M. Targeting hypoxia in cancer therapy. Nat Rev Cancer 11, 393–410 (2011). https://doi.org/10.1038/nrc3064

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