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

Abstract 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 ...