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Strategies to improve radiotherapy with targeted drugs

Key Points

  • Two complementary ways to improve radiotherapy are to increase the killing of tumour cells and to decrease damage to surrounding normal tissues. Central to success is finding and exploiting genetic or microenvironmental differences between normal and malignant tissues in each individual patient.

  • Modulating DNA repair: owing to genetic instability, tumours are often defective in one aspect of DNA repair but usually have backup pathways for accomplishing repair. Attacking these backup pathways can render the tumour radiosensitive while leaving the normal tissue relatively resistant. Increasing numbers of such examples are being discovered.

  • Modulating cell cycle checkpoints: tumours are often defective in one of the cell cycle checkpoints (such as the G1/S checkpoint). Inhibiting remaining checkpoints can leave tumours with less repair time, resulting in greater cell kill than in normal tissues.

  • Modulating signal transduction pathways: the PI3K–AKT, nuclear factor-κB (NF-κB), MAPK pathways and others, can all mediate radioresistance and are often aberrantly activated in tumours. Attacking these pathways with specific inhibitors is a promising avenue for increasing the radiosensitivity of tumours.

  • Modulating the microenvironment: tumours often contain radioresistant and chemoresistant hypoxic cells. Several methods are available to attack or exploit tumour hypoxia, leading to tumour-specific effects. Tumour vasculature can also be attacked in ways that increase the response to ionizing radiation.

  • Modulating normal tissue damage: a variety of strategies have shown promise in ameliorating ionizing radiation damage to normal tissues, including protection with radical scavengers, stimulating recovery with cytokines, modifying the p53 response, reducing the negative effects of inflammatory cascades and oxidative stress, and stem cell therapy.

  • The future: for any new strategies, it will be essential to define not only effects on the tumour but also effects on normal tissues. In addition, to realize personalized treatments, rapid and robust methods to assess deregulated pathways need to be developed. These then need to be combined with the development of a larger arsenal of agents inhibiting specific pathways, so that the most effective radiomodifying drug can be selected for each patient.

Abstract

Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. The dose of ionizing radiation that can be given to the tumour is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumour or to decrease the effects on normal tissues. These aims must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumour in the second approach. Two factors have made such approaches feasible: namely, an improved understanding of the molecular response of cells and tissues to ionizing radiation and a new appreciation of the exploitable genetic alterations in tumours. These have led to the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumour or normal tissue, leading to improvements in efficacy.

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Figure 1: Ionizing radiation-induced DNA damage repair.
Figure 2: Application of checkpoint inhibitors to increase the radiosensitivity of cancer cells.
Figure 3: Targeting signal transduction.
Figure 4: Targeting the microenvironment.
Figure 5: Strategies to reduce early or late ionizing radiation injury in normal tissues.

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Acknowledgements

The authors would like to thank the Dutch Cancer Society (KWF Kankerbestrijding) and the Netherlands Cancer Institute for long-term financial support.

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Correspondence to Adrian C. Begg.

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DATABASES

National Cancer Institute Drug Dictionary 

Amifostine

AZD7762

captopril

carbogen

cetuximab

cisplatin

efaproxiral

gefitinib

palifermin

pentoxifylline

tirapazamine

Glossary

Hypoxia

Lack of oxygen. Cells begin to become resistant to ionizing radiation at <1% oxygen (mild hypoxia) and are fully resistant at 0.01% oxygen (severe hypoxia). Solid tumours often contain a proportion of mildly and severely hypoxic cells.

Mitotic catastrophe

Caused by the attempt to segregate aberrant chromosomes. Failure of mitosis can activate programmed cell death (apoptosis). Problems completing mitosis and the resulting loss of genetic material can further reduce clonogenic survival.

Unfolded protein response

(UPR). A signalling cascade that is activated when unfolded or misfolded proteins are detected, which increases under hypoxia. It aims to stop protein translation and increase correct folding; failure can lead to cell death.

Electron affinic

A measure of the ability of a neutral atom to take up an electron. Oxygen is a powerful radiosensitizer because of its ability to capture electrons ejected by irradiation from DNA and other biomolecules, leaving them damaged and reactive and resulting in chemical bond breakage.

Hypofractionation

Conventional radiotherapy with curative intent is given in fractions of 1.8–2.0Gy daily on weekdays up to 30–35 times. Hypofractionation refers to giving a lower number of fractions larger than 2.0Gy, which is more effective per unit dose owing to the curvature of the ionizing radiation dose–response curve.

Hypoxia modification

The use of strategies to reduce the negative effect of hypoxia on the sensitivity to ionizing radiation, including selective killing or radiosensitization of hypoxic cells.

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Begg, A., Stewart, F. & Vens, C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 11, 239–253 (2011). https://doi.org/10.1038/nrc3007

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