Metabolic control of different responses of human cancer cells to X-ray and proton radiotherapy

Approximately 50% of all cancer patients are treated with ionizing radiations at least once during the course of
their disease,1 making of radiotherapy the second most frequent anticancer therapy after surgery. In Belgium,
photon radiotherapy (X-Rays and γ-Rays) has been in clinical use for cancer treatment since 1948.a
Comparatively, the first Belgian center of anticancer protontherapy opened in summer 2020.b A main advantage
of proton over photon radiotherapy is precise dose deposition in depth, owing to the nature of the beam itself
and to the possibility to use magnetic steering with ion beams.2 It notably allows sparing organs at risk (OARs).
A current disadvantage is the high cost of the technique. At the biological level, the efficacy of X-ray
radiotherapy and, probably to a lesser extent, of protontherapy,3,4 depends on the bioavailability of molecular
oxygen (O2) that stabilizes irradiation-induced DNA lesions.5 Despite the hypothesis that protons could induce
more direct lethal damage to DNA, the oxygen enhancement effect (OEE), i.e., the radiation dose required to
achieve a same biological effect, is around 2.5 to 3.0 for both photons and protons compared to 1.6 – 2.0 for
carbon ions.6,7 The OEE and hypoxia have thus been of great concern in the field from 1953,8 and many studies
including from our teams tried to optimize tumor oxygenation at the time of treatment.9-11 Poor tumor
oxygenation results from delivery issues due to aberrant tumor perfusion and is largely influenced by cancer cell
metabolism (oxidative versus glycolytic activities).12 Comparatively, the existence of other metabolic influences
has been largely understudied, especially for protontherapy. Yet, metabolism is at the core of the cancer disease,
as cancer cells strive to obtain sufficient nutrient ressources to survive, proliferate, migrate, invade and
metastasize.13-15 Our fundamental research project will use metabolically well-characterized cancer cell models
to identify and compare metabolic activities that would differently influence tumor responses to X-ray and proton radiotherapies using clinically relevant treatment regimen. Our working hypothesis is that (1) preexisting metabolic particularities of cancer and host cells could differently affect the response of tumors to X-rays and protons, and (2) both therapies could induce different metabolic changes resulting from cancer cell adaptation and selection, conditioning tumor cure, recurrence, and treatment-induced metastasis. Influences of the tumor microenvironment will be integrated by the use of organoids and in vivo models, together with the development of imaging techniques beyond the state of the art.