Description du sujet de thèse

Multimodal pretargeted radionuclide therapy of pancreatic adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is a cancer of unmet clinical need with a 5-year survival <10%. PDAC is notoriously difficult to treat due to its resistance to many therapies, and its characteristic dense stromal microenvironment. Therefore, there is an urgent need for the development of innovative therapies. Radiotheranostic, a rising field in nuclear oncology, enables the visualization of tumor biomarkers and the application of a complementary personalized therapeutic agent. It uses a tumor-targeting biomolecule (e.g. antibody, peptide, small molecule) labelled with a radionuclide for either diagnostic or therapeutic purposes. Alpha-particle targeted radionuclide therapy (-TRT) has shown promise due to its precision (short range), high linear energy transfer, and ability to overcome resistance to other therapies. Therefore, -TRT appears as an attractive strategy for the treatment of PDAC.
In this research program, we will focus on the development of -TRT approaches targeting complementary targets expressed in the neoplasm and stroma for a more personalized therapy of PDAC. We hypothesize that combining stromal and neoplasm-TRT could improve outcomes compared to monotherapies. The developed -TRT approaches will be based on antibodies. While effective biovectors for radionuclides, antibodies have limitations due to their long half-life, leading to toxicity. Pretargeting, an administration technique that separates the injection of the antibody from the cytotoxic radionuclide, has been shown to reduce off-target toxicity in previous preclinical studies, especially lowering hematotoxicity. The main objective of MULTI-PRIT (MULTI-Pretargeted RadioImmunoTherapy) project is to optimize a multimodal pretargeted radionuclide therapy approach for PDAC, leveraging the simultaneous targeting of both neoplastic and stromal targets to enhance therapeutic outcomes and reduce associated toxicities.

Contexte de travail

At ICMUB, PhD students benefit from working in an institute with long-standing expertise in chemistry and radiopharmaceutical development, providing a strong foundation for cutting-edge research in nuclear medicine. The institute offers a multidisciplinary environment that bridges fundamental discoveries with applied preclinical research. In partnership with IMATHERA (Preclinical Imaging and Radiotherapy Platform) at the Centre Georges François Leclerc (CGFL, Dijon), the recruited candidate will conduct his/her research in a unique setting equipped for advanced radiopharmaceutical development and evaluation. The facilities include well-equipped wet laboratories, with conventional labs for non-radioactive experiments, shielded labs for radiochemistry equipped with dedicated hoods for work with α-emitters or high-energy γ-rays, and shielded spaces for in vitro and in vivo experiments. The laboratory also provides access to state-of-the-art equipment essential for the completion of the proposed project, such as an HPLC system with UV and radioactive detector, dose calibrator, automatic gamma counter, digital autoradiography, animal blood cell counter, and a range of small animal imaging systems (bioluminescence/fluorescence imaging, µSPECT/CT, µPET/CT, and a fused PET/MRI scanner).

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Contraintes et risques

This research work is subject to strict regulatory constraints:
Radioprotection
Biological risks
Chemical risks