Opportunities and challenges of radiotherapy for treating cancer

Abstract

The past 20 years have seen dramatic changes in the delivery of radiation therapy, but the impact of radiobiology on the clinic has been far less substantial. A major consideration in the use of radiotherapy has been on how best to exploit differences between the tumour and host tissue characteristics, which in the past has been achieved empirically by radiation-dose fractionation. New advances are uncovering some of the mechanistic processes that underlie this success story. In this Review, we focus on how these processes might be targeted to improve the outcome of radiotherapy at the individual patient level. This approach would seem a more productive avenue of treatment than simply trying to increase the radiation dose delivered to the tumour.

Figures

Figure 1 |

The effect of the cell-cycle phase on radiosensitivity and on the DNA-repair pathway that is utilized. a | The schema shows how CDK1 engages HR in the S and G2 phase of the cell cycle, which coincides with an increase in radioresistance, at the expense of NHEJ. b | Progression through the cell cycle is under the control of a network of CDKs that rely on oscillating cyclin expression. Once a cell moves forward, out of G1 and into S phase, its DNA gets duplicated and therefore increasingly allowing for DNA damage repair to follow the more accurate route of HR. Abbreviations: CDK1, cyclin-dependent kinase 1; HR, homologous recombination; NHEJ, non-homologous end joining.

Figure 2 |

Possible mechanisms by which PARP-1 inhibitors might interact with radiation-induced DNA damage for therapeutic benefit. PARP inhibitors cause synthetic lethality in cells that have a compromised HR apparatus or can block cell survival pathways activated through NF-κB. On the left of the diagram, once PARP disassociates from the DNA complex, recruitment of repair proteins XRCC1 and DNA ligase III for repair of SSBs by BER commences; MRE11 and ATM facilitate DSB repair through HR. MRE11 also facilitates restart of stalled replication forks. The repair proteins help regulate chromatin structure, DNA methylation, histone H1 binding to chromatin, and transcriptional regulation of survival genes, such as NF-kB. Abbreviations: BER, base-excision repair; CD, C-terminal catalytic domain; DSB, double-strand break; HR, homologous recombination; NF-κB, nuclear factor κB; SSBs, single-strand breaks; PARP, poly(ADPribose) polymerase.

Figure 3 |

Redox and how it might influence both radiation responses and the immune system. The concept presented is that radiation-induced ROS/RNS drives the generation of a pro-oxidant state that results in acute inflammation, proinflammatory cytokines, more ROS/RNS production, and self-inflicted oxidative damage. At the same time, ROS has the ability to promote antigen presentation by DCs, TH1 cells, CTL and M1 macrophage responses, with further production of proinflammatory cytokines—all of which affirm the pro-oxidative state (left-hand side). The redox imbalance that is created eventually drives an antioxidant response (right-hand side) with increased glutathione synthesis, cell survival, and radioresistance. Under the same influences, immune-control mechanisms, including TREG cells, MDSC, M2 macrophages, and TH2 responses, as well as antioxidants and anti-inflammatory cytokines, will be favoured. Abbreviations: 2GSH, 2 monomeric glutathione molecules; CTL, cytotoxic T-cell lymphocyte; DC, dendritic cell; GSSG, glutathione disulphide; MDSC, myeloid-derived suppressor cells; Nrf2, nuclear factor (erythroid-derived 2)-like 2; ROS, reactive oxygen species; RNS, reactive nitrogen species; TH1, T-helper type 1 (cell); TH2, T-helper type 2 (cell); TREG, regulatory T (cell).