Combination of ionizing radiation and radio-enhancing molecules in breast cancer models
The proposed program aims to evaluate the efficacy of molecules enhancing the effects of radiotherapy, in models of breast cancer. Several molecules targeting and inhibiting the Base Excision Repair pathway will be tested for radiopotentiation efficacy in the in vitro and in vivo models.
The proposed inhibitors are already being investigated in vitro, both in the laboratory and by collaborators. We have shown that inhibition of the mechanisms targeted leads to an impairment in DNA damage repair following genotoxic stress. During this project, we will evaluate the effects of inhibitors on DNA damage repair induced by irradiation of different types (conventional, ultra-high dose rate, even extreme dose rate) and the associated mechanisms.
Variability in response to therapeutic combinations is frequently observed when moving from in vitro to in vivo models. We will therefore evaluate the inhibitors on cell line models well characterized in the laboratory, and corresponding to different breast cancer subtypes. On the other hand, the studies will be completed by a validation of the effects observed in vitro on a murine model of breast cancer. This xenograft model, developed in immunocompetent animals, will enable us to monitor the clinical, histological and immune response of the animals and their tumors, in order to confirm the interest of the molecules for therapeutic application in support of radiotherapy.
The proposed program will benefit from the laboratory's collaborations with physicists and chemists, and IRCM's experimental facilities and platforms (irradiation, animal experimentation, microscopy, cytometry, etc.).
Dynamic interplay of Rad51 nucleoprotein filament-associated proteins - Involvement in the regulation of homologous recombination
Homologous recombination (HR) is an important mechanism for the repair of ionizing radiation- induced DNA double-strand breaks. A key step in HR is the formation of Rad51 nucleoprotein filaments on the single-stranded DNA that is generated from these breaks. We were the first to show, using yeast as a model, that a tight control of the formation of these filaments is essential for HR not to induce chromosomal rearrangements by itself (eLife 2018, Cells 2021, Nat. Commun. 2025). In humans, the functional homologs of the yeast control proteins are tumor suppressors. Thus, the control of HR seems to be as important as the mechanism of HR itself. Our project involves the use of new molecular tools that allow a breakthrough in the study of these controls. We will use a functional fluorescent version of the Rad51 protein, developed for the first time by our collaborators A. Taddei (Institut Curie), R. Guérois and F. Ochsenbein (I2BC, Joliot, CEA). This major advance will allow us to observe the influence of regulatory proteins on DNA repair by microscopy in living cells. We have also developed highly accurate structural models of control protein complexes associated with Rad51 filaments. We will adopt a multidisciplinary approach based on genetics, molecular biology, biochemistry, and protein structure to understand the function of the regulators of Rad51 filament formation. The description of the organization of these proteins with Rad51 filaments will allow us to develop new therapeutic approaches.
Drug therapy for the management of radiation-induced hematopoietic and gastrointestinal syndromes
Nuclear technology is widely used in industry, army and medicine (diagnosis, radiotherapy and conditioning for transplants). Circumstances in which high-dose radiation exposure occurs can result in a considerable number of injuries and deaths in the absence of therapeutic intervention. These circumstances may include terrorism, accidents caused by nuclear reactor malfunctions, or radiotherapy accidents involving ionising radiation (IR) overdose. There are also medical cases of high-dose irradiation for the purpose of conditioning the patient for transplantation to treat certain diseases (acquired bone marrow failure, acute myeloblastic leukemia (AML) or hereditary aplastic anemia).
Exposure to high levels of radiation can quickly lead to acute radiation syndrome (ARS), which mainly affects hematological (blood, bone marrow) and gastrointestinal tissues in the hours, days and weeks that follow.
Hematopoietic syndrome (HS) is a major component of ARS. It develops after total body irradiation (TBI) at doses > 1 Gy and is characterized by partial or total destruction of bone marrow stem cells and their environment. The therapeutic management of HS is based on medical treatments using growth factors to stimulate residual hematopoiesis, but these may prove ineffective in cases of severe bone marrow damage. Hematopoietic stem cell transplantation is then the best treatment, but it is invasive, not always feasible due to a lack of donors, and its success rate remains extremely low, particularly due to severe side effects (risk of graft-versus-host disease).
Gastrointestinal syndrome (GIS) develops after a dose > 10 Gy (whole body or localized). It is characterized by weight loss, diarrhea and increased susceptibility to developing bacterial infections leading to septicemia. Death occurs within 5 to 12 days after irradiation. Current management is based solely on symptomatic treatments (antibiotics, anti-diarrhea drugs, anti-emetics).
It is therefore essential to develop new therapeutic methods to treat severely irradiated patients as quickly as possible after radiation exposure and with minimal side effects.
In this project, we propose to develop, through industrial and clinical collaborations, new drug therapies involving the administration of specific molecules to be tested in order to improve hematopoietic and/or intestinal recovery after irradiation.