Introduction: DNA Repair and Radiotherapy Targeting: An Overview

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This special issue of the Seminars in Radiation Oncology focuses on targeting DNA repair pathways in human tumors as a strategy for tumor cell radiosensitization. Key to this concept is the maintenance of the therapeutic ratio in which optimal killing of tumor cells will not be offset by increased killing of normal cells. One route to preserve this ratio is to document defects in DNA damage and repair pathways in tumor cells, which would confer selective sensitivity to ionizing radiation and targeted agents. The latter is particularly true for patients whose tumors, but not normal tissues, lack BRCA1 or BRCA2 function. These tumors have increased tumor cell sensitivity when challenged with poly (ADP-ribose) polymerase (PARP) inhibition because of “synthetic lethality,” and clinical trials using this approach have shown great promise. This issue of Seminars reviews these approaches in a state-of-the-art fashion by integrating the knowledge about genetic and microenvironmental factors into personalized medicine using DNA repair targeting agents combined with radiotherapy.

In the initial article, Bristow and Thoms review the importance of maintaining the therapeutic ratio as one targets DNA damage pathways and DNA repair. This serves as an overview for the issue to explaining general concepts relating to the use of genetic and microenvironmental predictors of DNA repair function to generate increased DNA damage in tumor tissues and spare normal tissue function. Understanding the intra- and interindividual differences in DNA repair is important and discussed by Saks and Stuschke in their discussion of the use of γH2AX as a biodosimeter in cancer patients undergoing fractionated radiotherapy or chemotherapy. They conclude that it is possible to estimate a therapeutic ratio using DNA repair foci in peripheral lymphocytes after radiotherapy or chemoradiotherapy protocols. Another predictor a priori of radiotherapy response could be inherent mutations within genes that are involved in the DNA damage and repair at the level of single nucleotide polymorphisms. Parliament and Murray develop the argument (and describe the caveats) towards the use of genome-wide association studies and massively parallel sequencing as novel technologies that can address radioresponse and normal tissues and tumors.

The next series of articles describe strategies to target specific DNA repair pathways as a means of tumor cell radiosensitization; Vens and Begg develop the rationale for targeting DNA base excision repair (BER). They review the data that associates defects in BER as a determinant of radiosensivity in vitro and describe specific BER proteins that can be targeted in proliferating tumor cells relative to nonproliferating normal tissues. It is of interest that a number of patients' tumors harbor mutations in DNA polymerase β that can be used as 1 predictor of response. Murkerjee et al take a different approach with the indirect targeting of nonhomologous end joining during DNA double strand break (DSB) repair by inhibiting epidermal growth factor receptor signaling. The combination of cetuximab with radiotherapy in head and neck patients led to increased local control and improvement in overall survival; the authors develop the argument that this, in part, was secondary to the effects of epidermal growth factor receptor signaling on DNA-PKc activity. Barker and Powell discuss targeting of the other major DSB repair pathway that of homologous recombination (HR). HR can be dysfunctional in many human cancers, and the authors discuss increased RAD51 and FANC proteins as a functional assay of HR after radiotherapy or chemotherapy. They summarize the data linking expression of HR proteins to radiocurability or response to chemotherapy and describe a number of ways to target HR to improve therapeutic response. This is followed by Udayakumar et al discussing crosstalk within the ATM-p53-MDM2-RB signaling pathways and DNA damage and repair. The authors describe the use of Radiation Therapy Oncology Group prostate cancer tissue microarrays as the genesis of novel prognostic factors in this pathway to assess outcome in patients having undergone radiotherapy ± androgen deprivation therapy. Furthermore, the authors describe potential inhibitors of these proteins, which could lead to increased tumor cell killing via altered tumor cell arrest and/or tumor cell apoptosis. Chalmers et al describe the concept of synthetic lethality as the basis for layering in PARP inhibitors into clinical trials of palliative and radical radiotherapy. They describe situations in which the inherent genetics, relative cell proliferation, tumor vascularity, and hypoxic fraction all may impact the success of combining PARP inhibition with fractionated radiotherapy.

Finally, the complexity of the tumor microenvironment with respect to the transcription and translation of DNA repair genes is described by Klein and Glazer. They point out that hypoxia can generate genetic instability and that defects in DNA mismatch repair and HR can give rise to increased sensitivity of repair-deficient hypoxic cells to a number of DNA damaging agents, including PARP inhibitors.

Overall, the articles in this special edition of Seminars in Radiation Oncology give a broad view of the direct and indirect ways to optimize interpatient differences in DNA repair and defects, sensitize tumor cells with specific DNA repair inhibitors, and augment DNA repair in normal tissues, all to improve the therapeutic ratio. For a number of these strategies, clinical trials are already underway, and the results are eagerly awaited as the basis for novel approaches to personalized medicine using precision radiotherapy.