Dbait: efforts continue
The key to effective treatment against cancer, is to target the tumor cells while preserving the healthy tissues. Radiotherapists must deliver a sufficient quantity of rays to damage the tumor without damaging the healthy tissues. But tumors are sometimes radio-resistant and a helping hand may be needed.
"As we sought to understand the resistance to radiation observed in almost 20% of patients, we developed small molecules that more or less resemble the damaged DNA," explains Marie Dutreix, CNRS director of research, head of the Recombination, repair, and cancer: from molecule to patient team (Inserm/CNRS/Institut Curie). "And so Dbaits were born. In practice, they act as “bait” within the cells. They trick cells into thinking that the quantity of damage to repair after radiotherapy treatment is much higher than is actually the case. The tumor cell, “overwhelmed” by the quantity of damage to be repaired, self-destructs."
During a phase-1 clinical trial, conducted between 2014 and 2016, it was shown that combining radiotherapy with the clinical form of Dbaits - AsiDNA™ - in local application, was effective and non-toxic. In terms of effectiveness, the complete response rate (disappearance of tumor nodules) was four times higher (37%) with Dbait molecules than what was reported in the past in the literature (9%) with radiotherapy alone.
Dbait and breast cancer
But the aim is to extend the indications, so that this innovation benefits as many patients as possible. To achieve this we need to evaluate the toxicity and effectiveness of combining Dbaits with radiotherapy for rare cancers, while sometimes leave doctors powerless. These include leukemia, lymphoma, myeloma, the most frequent hematological or "blood" cancers. Each year in France they affect more than 33,000 people, mostly at the start and end of life, namely children, young adults and the elderly. In an article published in December 2017 in the journal Molecular Cancer Therapeutics, Marie Dutreix and her team documented their study on the use of AsiDNA combined with radiotherapy on hematopoietic cells.
Ten lines of hematological tumor cells and healthy cells from donors were subjected to AsiDNA and ionizing radiation. The combination led to the death of the cancerous cell lines but had no significant impact on the blood cells or bone marrow. There seems to be a synergy for the effectiveness of these treatments.
New administration methods
With the first promising clinical results, other trials are already planned. A new clinical trial, led by Dr Christophe Le Tourneau, head of the department of D3i early trials (Department of Drug Development and Innovation), was launched in early 2018. It involves administering AsiDNA intravenously (and not applied locally as previously) to ensure that they are not toxic. "If results show that intravenous administration is not toxic, we can hope to be able to launch a phase-2 clinical trial by the end of next year," explains Marie Dutreix.
The DNA Repair Inhibitor Dbait Is Specific for Malignant Hematologic Cells in Blood
Sylvain Thierry, Wael Jdey, Solana Alculumbre, Vassili Soumelis, Patricia Noguiez-Hellin and Marie Dutreix, Molecular Cancer Therapeutics, December 2017