PhD thesis defense in physical sciences by Lucas Schoenauen

Development and characterisation of a UHDR irradiation station on ALTAÏS: C. elegans as a new potent model for FLASH investigation 

Candidate

Lucas Schoenauen

Promoters

Prof. Anne-Catherine Heuskin, UNamur, Department of physics, Physics of Matter and Radiation (PMR), Laboratory of Analysis by Nuclear Reaction (LARN) - promoter

Prof. Stéphane Lucas, UNamur, Department of physics, Physics of Matter and Radiation (PMR), Laboratory of Analysis by Nuclear Reaction (LARN) - co-promoter

Jury

• Carine Michiels, présidente (URBC, UNamur)
• Rudy Labarbe (Ion Beam Application, Louvain-la-Neuve)
• Simon Galas (IBMM, Université de Montpellier)
• Joao Seco (DKFZ, German Cancer Research Center, Heidelberg University)
• Anne-Catherine Heuskin (LARN, UNamur) 
• Stéphane Lucas (LARN, UNamur)

Summary

Radiation therapy remains a cornerstone of cancer treatment, yet normal‑tissue toxicity continues to limit dose escalation and therapeutic benefit. In recent years, ultra‑high dose rate (UHDR) irradiation, known as FLASH radiotherapy, has demonstrated a remarkable normal‑tissue sparing effect while maintaining tumor control. Despite increasing preclinical and early clinical evidence, the biological mechanisms underlying this effect remain poorly understood, and systematic investigation is hindered by limited access to UHDR‑capable irradiation platforms.

The first objective of this thesis was, therefore, to develop and characterize a dedicated UHDR irradiation platform on the ALTAÏS accelerator at the University of Namur. This platform enables precise control of dose rate and temporal beam structure, enabling irradiation with protons and alpha particles over a broad linear energy transfer (LET) range. The new UHDR setup consists of a dosimetric system based on a homemade Faraday cup, a beam profiler to assess spatial beam homogeneity, and a µ-pulser capable of delivering pulses down to 10 µs. With this setup, both CDR and UHDR irradiations are now routinely achievable on ALTAÏS at the LARN laboratory.

The second objective was to identify and validate a suitable in vivo biological model compatible with the physical constraints of the ALTAÏS platform. Caenorhabditis elegans was selected as a novel FLASH model due to its small size, genetic tractability, short life cycle, and well‑characterized biology. A proof of concept demonstrated that embryonic irradiation induces a measurable growth delay in adulthood and that this endpoint exhibits a clear FLASH‑associated sparing effect following both proton and electron UHDR irradiation.

Subsequently, the influence of LET on the magnitude of the FLASH effect was investigated using proton and alpha beams with LET values ranging from 10 to 100 keV/µm, i.e., 4 MeV protons (10 keV/µm), 1.5 MeV protons (25 keV/µm), and 6 MeV alphas (100 keV/µm). Although a FLASH-associated sparing effect was consistently observed across all particle types, no clear correlation between LET and sparing magnitude could be established. Behavioural endpoints, such as crawling and thrashing, showed high variability and limited sensitivity, emphasizing the importance of robust endpoint selection and sufficient sample sizes when investigating subtle FLASH‑associated effects.

Finally, to directly assess neurotoxicity, dendritic development of the PVD nociceptor neuron was investigated following embryonic irradiation. UHDR irradiation preserved early dendritic arborization compared with CDR exposure, providing the first direct evidence of a FLASH‑associated neuroprotective effect in a non‑rodent in vivo model. This finding supports C. elegans as a complementary model for mechanistic neuroprotection studies prior to validation in mammalian systems.

Overall, this thesis establishes both a novel UHDR irradiation platform at the University of Namur and a new high‑throughput in vivo model for FLASH research. Together, these developments open the way to systematic investigations of FLASH‑associated sparing mechanisms, including neuroprotection and LET dependence, with reduced experimental complexity, cost, and ethical burden.