CE18 - Innovation biomédicale

Identification of innovative NHEJ inhibitors – NEJIN

Submission summary

Most anti-cancer treatments aim at generating burst of DNA double strand breaks (DSBs), the most toxic DNA lesion. Several drawbacks are associated with these therapies: (i) their inherent toxicity, (ii) the relapse when the cancer stem cell is not shattered, and (iii) the emergence of resistance to treatment. A major challenge is to couple radiotherapy and radiomimetic treatments with adjuvent molecules impacting on the DNA damage response (DDR) to enhance the genotoxic strength while minimizing the toxicity. Based on our knowledge of the DDR, we propose an innovative approach to uncover potent in vitro inhibitors of the Non-Homologous End Joining (NHEJ) DNA repair pathway through functional screens with the following rationale:
• NHEJ is the sole DNA repair pathway that copes with DSBs occurring in G0/G1 arrested cells. This project thus offers a unique opportunity to identify drugs targeting the characteristics of stem cells including cancer stem cells.
• Few physiological processes strictly rely on NHEJ thus providing a basis for the design of specific functional screens.
• We identified a previously unknown physiological NHEJ backup systems resulting in "synthetic dysfunction" when defective. This mechanism, when present in a tumor, may participate in resistance to treatments.
The deliverable of our project will be a list of optimized molecules that specifically counteract NHEJ, with the intend to exploit them as radiosensitizer in anti-cancer treatments. This project will also deepens our scientific understanding of the DDR as a whole, through the precise identification of key steps impacted by these new inhibitors.
This project is based on a close collaboration between three academic laboratories and a biotechnology company around an ambitious and innovative R&D project. It represents a unique opportunity to integrate complementary expertise in cellular and structural biology as well as in chemistry and drug modeling on a major public health issue.

Project coordination

Jean-Pierre DE VILLARTAY (INSTITUT DES MALADIES GÉNÉTIQUES (IHU))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

JOLIOT Institut des sciences du vivant FRÉDÉRIC-JOLIOT
MEDETIA
I2BC Institut de Biologie Intégrative de la Cellule
IMAGINE INSTITUT DES MALADIES GÉNÉTIQUES (IHU)

Help of the ANR 541,276 euros
Beginning and duration of the scientific project: December 2023 - 24 Months

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