Radiation therapy (RT) is widely used in cancer care strategies. Its effectiveness relies mainly on its ability to cause lethal damage to the DNA of cancer cells. However, some cancers have shown to be particularly radioresistant partly because of efficient and redundant DNA repair capacities. Therefore, RT efficacy might be enhanced by using drugs that can disrupt cancer cells' DNA repair machinery. Here we review the recent advances in the development of novel inhibitors of DNA repair pathways in combination with RT. A large number of these compounds are the subject of preclinical/clinical studies and target key enzymes involved in one or more DNA repair pathways. A totally different strategy consists of mimicking DNA double-strand breaks via small interfering DNA (siDNA) to bait the whole DNA repair machinery, leading to its global inhibition.

Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of "palliative" RT (10 × 3 Gy) or "radical" RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the "palliative" protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67 days] or the "radical" protocol (TGD by 3.2-fold; median survival: 221 vs 109 days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial).

In the present study, we have evaluated the efficacy and toxicity of repeated brain metastases (BM) stereotactic radiosurgery (SRS2) following local failure of a prior radiosurgical procedure (SRS1). Between December 1996 and August 2015, 30 patients with 36 BM underwent SRS2 with a median dose of 18Gy. All BM were located outside critical structures. Following SRS2, local control at 6 months and one year were respectively 82.9% (IC 95%: 67.6–91.9) and 67.8% (IC 95%: 51–81). On multivariate analysis, planning target volume (PTV) < 3cc (HR: 0.19 (0.1–0.52)) and whole brain radiotherapy (WBRT) prior to SRS2 (HR: 0.25 (0.1–0.64)) were significantly associated with a better local control. One- and two-year overall survival rates after SRS2 were respectively 65.5% (IC 95%: 47.3–80%) and 27.6% (IC 95%: 14.7–45.7). Median overall survival following SRS2 was 14.2 months (range 1–106). Nineteen (63%) patients died from progressive systemic disease. Three (10%) patients died from out-field progressive brain disease and 8 (27%) in-field. Concerning toxicities, edema, radionecrosis, and hemorrhages were identified in 5 (12.8%), 4 (10.2%), and 5 (12.8%) patients respectively. No toxicity resulted in a neurological deficit. On univariate analysis, toxicities were significantly associated with PTV > 7cc (p = 0.02) and all patients had a WBRT before SRS2. A second course of SRS for locally recurrent brain metastases showed encouraging rates of local control. This treatment led to acceptable toxicities, especially for brain metastases smaller than 7cc, in our selected cohort of patients with BM located outside critical structures. Further studies are needed.