Scientific advancement and proofs of concept
DNA Therapeutics’ first molecule Dbait currently under early stage preclinical development, targets the non homologous end joining (NHEJ) DNA repair pathway which is the main DNA repair mechanism of the most lethal double strand DNA breaks (DSB).
The bioactivity of Dbait molecules has been extensively investigated in vitro and in vivo. Their chemical structure and size have been optimized. Their interaction with proteins involved in the NHEJ DSB repair pathway has been proven in vitro. The proofs of concept of Dbait have been achieved in four human tumors xenografted onto nude mice by local or systemic administration in association with radiotherapy, and in spontaneous intestinal tumors in genetically engineered mice by oral or intraperitoneal administration in association with chemotherapy.
Figure below illustrates the efficacy of Dbait in association with radiotherapy (RT) in nude mice xenografted by human Head & Neck squamous cell carcinoma (HNSCC).
A human radio-resistant head & neck squamous cell carcinoma (HNSCC) was subcutaneously xenografted on nude mice. Treatment started when the tumors were about 200 mm3 in volume. Dbait molecules were administrated by intratumoral injection 5 hours prior RT at 2Gy/session. The treatments were repeated 3 times a week (every other day) for 5 weeks. Upper left: Overall survival curves (Kaplan-Meier plot): 4 arms were tested (11-23 mice/arm): untreated; RT alone; RT + increasing dose of Dbait. Upper right: Statistical analysis of the data: RT arm was used as reference (C) for hazard ratio (HR) and p-value calculation. Bottom: Magnetic resonance imaging at mid-course of treatment showed an enhanced necrosis (light gray area) in the xenografted tumor (white circle) in the presence of lowest dose of Dbait as compared to RT alone. Double blinded histological analysis confirmed the enhanced necrosis and apoptosis.
Significant increases of tumor growth delay and of survival have been observed, including complete tumor regression without reoccurrence after more than 300 days, following the administration of Dbait molecules in tumors and combined with fractionated radiotherapy regimens.
Biomarkers specific of Dbait's bioactivity have been identified and are under development.
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