A Preclinical Study Combining the DNA Repair Inhibitor Dbait with Radiotherapy for the Treatment of Melanoma

Abstract

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).

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

“…This pharmacological form called AsiDNA (or DT01), has been tested in phase I clinical trial on melanoma in association with radiotherapy. Two studies show the selective increase of cancerous cells sensitization [39,40]. Preclinical studies showed a chemo-sensitization of metastatic colorectal and liver cancers with AsiDNA [41].…”

The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis

“…11). We demonstrated that local administration of DT01 by intratumoral injection in association with radiotherapy increases survival of xenografted human melanoma models (13). However to date, the efficacy of systemic administration of DT01 in association with chemotherapy has not been investigated.…”

“…We previously showed Dbait to be effective in combination with radiotherapy on several radio-resistant tumors, both in vitro and in vivo (8,(11)(12)(13). Furthermore, studies on an intestinal tumor rodent model revealed that oral administration of Dbait, in association with the chemotherapy agents 5-fluorouracil and camptothecin leads to increased chemosensitization of intestinal tumors and to a low systemic exposure (14).…”

Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors

“…AsiDNA acts by hijacking and hyper-activating PARP1 (13) and the DNA-dependent protein kinase (DNA-PK) (14) which modify the chromatin and consequently inhibit the recruitment of many proteins involved in the HR and NHEJ pathways at the damage sites (14). This strategy sensitizes tumors to DNA damaging therapies such as radiotherapy and chemotherapy (15)(16)(17)(18). The first-in-human phase I trial, combining AsiDNA to radiotherapy to treat patients with skin metastases from melanoma showed encouraging results, with 30% of complete responses (19).…”