Research
Radiobiology and Targeted Radiotherapy : JP. Pouget

Research topics

 

Our work is organized around different fields

 

Development of vector molecules: We have developed murine, chimeric or humanized monoclonal antibodies (mAbs) directed against the anti-Müllerian hormone receptor (MISRII) overexpressed in ovarian cancers. In the context of an industrial partnership we are also involved in the development of an anti-CD37 mAb directed against non-Hodgkin's B lymphoma cells. Finally, in the framework of an academic collaboration, we develop a two-step pre-targeting approach (using bio-orthogonal chemistry) of colorectal cancer cells expressing carcinoembryonic antigen (CEA). This first line of research benefits in particular from the support of Labex MabImprove.

 

Development of Radiopharmaceuticals (ARC, ARDC): The vector molecules developed are then coupled to either beta (177Lu), alpha (212Pb / 212Bi, 213Bi, 225Ac) or Auger (125I, 195mPt / 193mPt) emitting radionuclides used in therapeutic purposes or to gamma or beta + (89Zr, 111In) radionuclides for diagnostic purposes. The radiopharmaceuticals obtained are called antibody radiolabeled conjugate (ARC) or antibody radiolabeled drug conjugate" (ARDC) when they are using radioactive platinum (carboplatin) compounds

 

                                                                  

 

Targeting properties assessment: The targeting qualities and pharmacokinetic data of the new radiopharmaceutical are evaluated using imaging techniques at the cellular (immunofluorescence), tissue (digital autoradiography) or organism level (SPECT / PET). Our team is in charge of the small animal imaging platform SPECT / CT and PET / CT of the IRCM.

 

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.

 

 

 

Evaluation of the therapeutic efficacy: at the cellular as well as tissue and organisms level, the search for a high therapeutic gain thanks to the new developed radiopharmaceuticals remains our primary objective.

 

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.

 


© Institut de Recherche en Cancérologie de Montpellier - 2011 - Tous droits réservés - Mentions légales - Connexion - Conception : ID Alizés