Our research work is organized around different fields constituting a rationalized approach in targeted radionuclide therapy:
Development of radiopharmaceuticals (ARC, ARDC) directed against ovarian peritoneal carcinosis: We have developed preclinical model, chimeric and humanized monoclonal antibodies (mAbs) directed against the anti-Müllerian hormone receptor (MISRII) overexpressed in ovarian cancers.
Resulting molecules are then coupled either to beta (177Lu), alpha (212Pb / 212Bi, 213Bi, 225Ac) or Auger (125I, 195mPt / 193mPt) radionuclides for therapeutic purposes or to beta+ (89Zr, 68Ga) or gamma (111In)radionuclides, for diagnostic purposes. The radiopharmaceuticals obtained are called "antibody radiolabeled conjugate" (ARC) and more specifically "antibody radiolabeled drug conjugate" (ARDC) when they involve chemotherapy drug, namely carboplatin containing radioactive 195mPt or 193mPt.
Therapeutic efficacy as well as possible side effects are then assessed both at the cellular and preclinical model levels. This first line of research benefits in particular from the support of the Labex MabImprove.
Biodistribution and dosimetry of radiopharmaceuticals: The targeting abilities as well as the biodistribution of new radiopharmaceuticals are evaluated using cellular (immunofluorescence), tissue (digital autoradiography) or non-invasive in vivo imaging techniques (SPECT / PET). These data are then used to support dosimetric studies.
Our team is also in charge of the IRCM’s SPECT / CT and PET / CT small preclinical model imaging platform.
Study of the radiobiological mechanisms involved: The optimization of the treatments by TRT requires to understand the mode of action of the ionizing radiations in a context of irradiation with low rate of dose, prolonged on several days and delivering very heterogeneous doses in the body, the tissues and up to the cellular level. We are particularly interested in the contribution of targeted (purely radiative) and non-targeted effects observed in cells not directly irradiated by radiopharmaceuticals. These include "bystander" effects involving short-distance intercellular communications and abscopal (also referred to as systemic) effects involving activation of the immune system. We have demonstrated the involvement of membrane lipid rafts in the targeted and non-targeted cytotoxic mechanisms of RTV Auger and alpha. Lipid rafts are membrane domains enriched in ceramide and cholesterol and also containing various proteins. Their formation is accompanied by the activation of signaling pathways involving the p38 / JNK proteins involved in cell death. The ceramide is itself formed by hydrolysis of sphingomyelin, a membrane sphingolipid, under the action of acid sphingomyelinase, itself activated by reactive oxygen species produced by irradiation.
We have shown that drugs that modify cholesterol metabolism and thus lipid raft formation may reduce the effectiveness of RTV.
The identification of the factors secreted by the irradiated cells and communicated to the neighboring cells, as well as their possible role in the activation of the immune system is part of the research field that we are developing within the SIRC Montpellier.
Study of therapeutic associations:
The study of the radiobiology of TRT has allowed us to define therapeutic associations that optimize the effectiveness of TRT. This is the case of G2/M cell cycle arrest inhibitors, immune checkpoint inhibitors or combination with radiosensitizing nanoparticles.
Translation to the clinic:
The final aim of our research, led by a multidisciplinary team including nuclear physicians, physicists and radiopharmacists from the ICM Nuclear Medicine Department, is to be transferred to the clinic for optimal cancer diagnosis and treatment.