Research
Radiobiology and Targeted Radiotherapy : Jean-Pierre POUGET & David AZRIA

•    Radiobiological studies and therapeutic combinations. This is the core of our expertise. Specifically, we investigate in preclinical models and in patients the relative contribution of both targeted effects (observed in irradiated tissues) and non-targeted effects (observed at a distance). Non-targeted effects implicate bystander cytotoxicity and bystander immunity. Our aim is to understand how TRT modulates damage (DNA, cell membrane) in irradiated cells and how this information is communicated to neighboring tumor or microenvironment cells through the release of extracellular vesicles that participate in cGAS-STING pathway activation. We demonstrated that in cultured cells, ceramide-enriched large domains formed at the surface of TRT-irradiated cells actively participate in extracellular vesicles formation and in the bystander response. We also showed that cholesterol metabolism-modifying drugs alter lipid raft formation and reduce TRT effectiveness in this model.

•    Theranostic properties of radiopharmaceuticals targeting tumor cells or the tumor microenvironment. We use commercially available radiopharmaceuticals and radionuclides (177Lu-DOTATATE, 223RaCl2) and also new radioimmunoconjugates (i.e. radiolabeled antibodies or peptides) to target tumor cells or their microenvironment (e.g. cancer-associated fibroblasts) as TRT modalities in preclinical cancer models. We are also developing home-made radiopharmaceuticals to target i) anti-Müllerian hormone receptor II (MISRII), which is overexpressed in ovarian cancers, for treating peritoneal carcinosis from ovarian cancer;  and ii) the nucleus of cancer cells with Auger electron emitters. For therapy, vectors are radiolabeled with alpha (225Ac, 213Bi, 212Bi), beta (177Lu), or Auger electron (125I, 195mPt, 111In) emitters.

•    Nuclear imaging, MRI and multiscale dosimetric approaches. We assess the targeting properties and the pharmacodynamic and pharmacokinetic (biodistribution) features of radiopharmaceuticals in preclinical models at the cellular, tissue, and whole body scale using invasive (digital autoradiography) and non-invasive  small-animal imaging techniques (SPECT/CT, PET/CT). We then use the obtained imaging data for radiomics analyses or absorbed dose assessment. We are developing and optimizing a similar approach also for clinical studies. This will allow to explore large  volume of imaging data and to integrate them with tumor biology and tumor response to radiotherapy

•    Prediction of radiation-induced toxicity in patients with cancer using the RILA test. The study of EBRT-induced effects in healthy tissue has been one of our expertise fields since 1996. We have organized several prospective clinical trials to assess the predictive value of the radiation-induced lymphocyte apoptosis assay (RILA) to prevent EBRT late side effects. Today, the validated RILA assay is used in several clinical trials at ICM.

•    Understanding the mechanisms of lymphocyte radiosensitivity or radio-resistance: To unravel RILA molecular mechanisms, we assess differences in lymphocyte subtype distribution in patients with cancer with and without late radiation-induced toxicities. We also study the lymphocyte radiation-induced apoptosis signaling pathways in patients with and without late radiation-induced toxicities.
•    Translational Research: A growing part of our research activity focuses on the analysis of data and samples collected from patients treated with TRT to set up a bench-to-bedside and bedside-to-bench approach. This will allow to identify markers of tumor response to TRT and decipher how TRT modulate intercellular communications such as those involved in immune response activation. Moreover, the possibility to predict (RILA) the radiosensitivity of each patient receiving EBRT will allow proposing a better adapted treatment according to the toxicity risk and to treat patients in a more personalized way. In the longer term, it will also provide us with elements for understanding the development of radiation-induced toxicities.