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

Axis 1 : Developing clinical radiobiology (Principal investigator: J Constanzo/E Deshayes/V Boudousq/J-P Pouget)

We are studying the dose-response relationship in patients treated with TRT or the combination of TRT+EBRT by analyzing dosimetry, lesion response, toxicity, and clinical patient data. Building on previous work carried out with ICM and the CHU of Nîmes, we are expanding our Translational Research Program (https://immunoriv.fr/) involving patients treated for neuroendocrine or metastatic thyroid tumors with ¹⁷⁷Lu-DOTA-TATE or ¹³¹I to new cohorts of patients treated with ¹⁷⁷Lu-PSMA (prostate and kidney cancer) and ¹⁷⁷Lu-anti-CXCR4 (bladder cancer). Using immune profiling, histological data, from the analysis of circulating extracellular vesicles and single-cell RNA sequencing, we aim to predict the efficacy of TRT based on the dose absorbed by the lesions and the immune response, in order to define optimal thresholds for preserving and activating the immune system.

Axis 2 : Deciphering immunostimulatory effects of targeted radionuclide therapy  (Principal investigator: T David/J Constanzo)

Our goal is to explore the influence of the radiation dose, its fractionation, and the nature of the radiation on the immunostimulatory effects of TRT. The studies focus on preclinical models of ovarian cancer, PDAC models, or prostate cancer targeted by radioligands (anti-HER2/HER1 or anti-MISRII monoclonal antibodies, anti-FAP sdAb, or PSMA) previously coupled with beta, alpha, or Auger-emitting radionuclides. The study of the immune system's involvement is based on the analysis of DAMPs released by irradiated cells or phenotypic activation markers measured by single-cell RNA sequencing or immune profiling.

Axis 3: Role of DNA damage and of extracellular vesicles in the response to TRT (Principal investigators: J Constanzo/J-P Pouget)

We are studying the role of cytosolic double-stranded DNA (dsDNA) and extracellular vesicles (EVs) in the immunomodulatory effects of TRT. To do this, we investigate the formation of DNA fragments, their origin (mitochondrial/genomic), size, and sequence in cells exposed to different types and doses of TRT. Preclinical models deficient in CGAS/STING pathways, or for TREX-1 or DNase1L3 proteins, also allow us to further explore the role of these actors in the immunomodulatory or cytotoxic effects of TRT modulated by EVs.

Axis 4: Developing theranostic approaches of cancer (Principal investigators: J-P Pouget/E Deshayes)

Our research develops theranostic approaches for ovarian cancer through preclinical models (program accredited by the League Against Cancer, http://ovariv.fr/) using:

1. anti-MISRII antibodies. Building on previous work leading to the development of Murlentamab™ for immunotherapy, we have developed several humanized anti-MISRII monoclonal antibodies as candidates for beta, alpha, or Auger radiation therapy.
2. nanoparticles (NPs) used alone in radioactive form (https://www.akenmedical.com/) or in combination with beta or alpha TRT (gadolinium NPs).
3. anti-FAP nanobodies targeting cancer-associated fibroblasts (collaboration with PRECIRIX, Belgium), used alone in beta or alpha TRT or in therapeutic combinations.

Axis 5: Integrated combinatorial approaches in prostate and pancreatic cancers
(Principal investigators: M. Brengues / J.-P. Pouget / D. Azria)

This integrated approach explores the combination of TRT, EBRT, and chemotherapy in the treatment of prostate and pancreatic cancer. The study aims to optimize treatment sequences, radiation types, and doses, and to investigate how they positively modulate immune responses. This research is part of Axis 1 (IRP-1) of the SIRIC Montpellier program (https://montpellier-cancer.com/). It is complemented by the development of a virtual biopsy for cancer based on multimodal imaging and biological parameters, enabling personalized and optimized radiotherapy approaches. The ultimate goal is to improve patient selection, predict treatment responses, and explore new therapeutic combinations.

Axis 6: Quality assurance in clinical dosimetry (Leaders: M. Bardiès / L. Santoro / B. Piron)

The team is developing OpenDose3D (https://www.youtube.com/@OpenDose3D), an open-source clinical dosimetry software that enables software comparisons, clinical studies and the aggregation of data obtained by different approaches.  The identification of variables to ensure dosimetric traceability is being studied within EFOMP working groups (https://www.efomp.org/index.php?r=pages&id=sig-frid). The aim is to define a DICOM standard suitable for molecular radiotherapy. The generation of virtual patients (digital twins), in collaboration with the École des Mines d'Alès, will enable us to characterize the variability of clinical dosimetry. An emerging research theme concerns multimodal irradiation, with the superimposition of absorbed dose maps for treatments combining internal/external irradiation.