Combined Treatment Modalities for High-Energy Proton Irradiation: Exploiting Specific DNA Repair Dependencies

DNA repair deficiencies and genome instability are common features and hallmarks of cancer and are ubiquitously found in the full spectrum of malignant diseases. Heritable DNA repair deficiencies, for example, due to BRCA1 and BRCA2 mutations, and subsequent loss of heterozygosity in mammary, ovarian, and prostate carcinoma, are risk factors for the early development of cancer. Despite their detrimental role in tumorigenesis, these deficiencies also provide novel opportunities for treatment options. Current and future pharmacologic approaches in medical oncology rely on the exploitation of such genetically defined, tumor-specific Achilles' heels and integrate the genetic background of a tumor into the treatment strategy. For example, homologous recombination-corrupted, BRCA1/2-mutated tumors are becoming hypersensitive to inhibitors of an additional DNA-damage-repair mechanism and are successfully treated with respective molecular targeting agents such as PARP1 inhibitors. Patient stratification in radiation oncology today is primarily based on clinical parameters and uses highly sophisticated diagnostic imaging for treatment planning on the individual level. Radiation oncology only minimally takes the genetic makeup of tumors into account, and little attention has been given to the fact that the different modalities of ionizing radiation, such as photon and proton irradiation, may also induce differential damages and biological processes, which might again be influenced by the genetic makeup and mutational status of the tumor. However, radiation oncology is nowadays challenged to understand subtle differences induced by the different qualities of ionizing radiation, and to efficiently exploit and to integrate these differential responses in a personalized treatment approach alone and as part of combined treatment modalities with pharmacologic agents. Here we will review recent insights on the differential DNA damage responses to photon and proton irradiation and discuss their implications for combined treatment modalities with chemotherapeutical agents and small molecular targeting compounds.