MetaRad Project
Approximately 50% of all cancer patients are treated with ionizing radiations at least once during the course of their disease, 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. Comparatively, the first Belgian center of anticancer protontherapy opened in summer 2020. 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. 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, depends on the bioavailability of molecular oxygen (O2) that stabilizes irradiation-induced DNA lesions. 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. The OEE and hypoxia have thus been of great concern in the field from 1953, and many studies including from our teams tried to optimize tumor oxygenation at the time of treatment. Poor tumor oxygenation results from delivery issues due to aberrant tumor perfusion and is largely influenced by cancer cell metabolism (oxidative versus glycolytic activities). 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. 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.
Our project is divided in 3 work packages (WPs). All WPs are complementary yet independent enough to perform several tasks simultaneously. They offer time flexibility with respect to key intermediate findings. WP1 focuses on models and protocols. It aims (1) to develop clinically relevant irradiation protocols that will be finely tuned according to in vitro and in vivo findings, (2) to generate metabolically relevant cancer cell models, and (3) to develop a unique toolbox simultaneously providing quantitative data on the redox status, OCR, hypoxia and metabolism in vitro and in vivo. WP2 focuses on biochemistry. It aims to (1) identify different metabolic pathways in cancer cells conditioning the response to X-Ray and/or proton irradiation, as well as specific metabolic changes in response to therapy; and (2) assess the metabolic influences of the tumor microenvironment on radioresistance. WP3 focuses on cancer cell phenotypes related to tumor control. Still comparing X-Rays to protons, we will test (1) whether or not these treatments induce cancer stemness responsible for tumor recurrence, and (2) whether or not they trigger cancer cell EMT, migration, invasion and metastasis. We expect that X-Ray compared to proton irradiation and low dose compared to high dose regimens will be more susceptible to trigger aggressive cancer cell behaviors. By comparing X-Ray to proton radiotherapies, we further expect to identify rationales to adapt irradiation protocols and/or new targets for combined therapy. Our ultimate goal is that this fundamental research project could later be translated to optimize tumor cure.
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.
Our project is divided in 3 work packages (WPs). All WPs are complementary yet independent enough to perform several tasks simultaneously. They offer time flexibility with respect to key intermediate findings. WP1 focuses on models and protocols. It aims (1) to develop clinically relevant irradiation protocols that will be finely tuned according to in vitro and in vivo findings, (2) to generate metabolically relevant cancer cell models, and (3) to develop a unique toolbox simultaneously providing quantitative data on the redox status, OCR, hypoxia and metabolism in vitro and in vivo. WP2 focuses on biochemistry. It aims to (1) identify different metabolic pathways in cancer cells conditioning the response to X-Ray and/or proton irradiation, as well as specific metabolic changes in response to therapy; and (2) assess the metabolic influences of the tumor microenvironment on radioresistance. WP3 focuses on cancer cell phenotypes related to tumor control. Still comparing X-Rays to protons, we will test (1) whether or not these treatments induce cancer stemness responsible for tumor recurrence, and (2) whether or not they trigger cancer cell EMT, migration, invasion and metastasis. We expect that X-Ray compared to proton irradiation and low dose compared to high dose regimens will be more susceptible to trigger aggressive cancer cell behaviors. By comparing X-Ray to proton radiotherapies, we further expect to identify rationales to adapt irradiation protocols and/or new targets for combined therapy. Our ultimate goal is that this fundamental research project could later be translated to optimize tumor cure.