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Description
This project will develop novel approaches for treating a highly invasive cancer that responds poorly to treatments. Glioblastoma is the most frequent and deadliest form of brain cancer and represents a major health problem affecting many young children. Radiotherapy plays a crucial role in glioma treatment, however, glioma cells survive the treatment, one underlying reason being the presence of cancer stem cells that have high DNA repair capacity.
One promising strategy to improve treatment is therefore to combine radiotherapy with inhibitors of DNA repair. We aim at identifying radiation-drug combinations inhibiting DNA repair and exploring how such treatment combinations work in cells irradiated with high versus low radiotherapy . We also aim at identifying new promising biomarkers signatures that may support the development of personalized treatment of patients.
An original approach will be employed by using a new DNA repair high-throughput drug screening, unique in the world, available at Norwegian partner, to identify drugs that could be used as glioma radiosensitizers in association with conventional low-LET and with high-LET particle therapy.
The society will benefit through the development of new and better strategies to treat cancer.
The expertise of the Romanian team will be highly enhanced in the topic of mechanisms driven the DNA repair following the radiotherapy procedure and the Norwegian researchers will be better prepared for exploiting a new proton radiotherapy centre (to be opened in 2023). The outcome of the project will allow a good chance to develop new long-term collaborations with hospitals that could be end-users.
Summary of project results
Glioblastoma is the most frequent and deadliest form of brain cancer and represents a major health problem affecting many young children. The median overall survival is limited to 12-18 months following diagnosis despite continuous improvements in treatment. Radiation therapy plays a crucial role in glioma treatment, however, glioma cells survive the treatment, one underlying reason being the presence of cancer stem cells that have high DNA repair capacity. The DORADIOS aimed to develop new efficient strategies for glioblastoma radiosensitization. We aim at identifying highly efficient radiation-drug combinations inhibiting DNA repair and exploring how such treatment combinations work in cells irradiated with high-LET (protons and carbon-ions) versus conventional low-LET (X-rays) radiotherapy.
DORADIOS involved two partners (IFIN-HH, Romania; OUH, Norway) and also two collaborators (CEA, CAEN, France; DMU, Leicester, UK) to: identify drugs that inhibit DNA repair/G2/M checkpoint after radiation in glioblastoma cells using high-throughput screening technology; validate candidate anti-glioma drugs that radiosensitize the tumor and comparison of effects with high-LET versus low-LET irradiation; elucidate molecular mechanisms of DNA repair that may control radioresistance/radiosensitivity balance; do pan-omic analysis: transcriptomic, metabolomic and proteomic) in glioblastoma cells treated with selected combinations of radiotherapy and drugs, to likely identify new possible predictive biomarkers for radiosensitivity. The most important results included: two DNA repair inhibitors proved to be good radiosensitizers of glioblastoma cells to X-ray, proton and carbon ion radiation; ATR inhibition can increase antitumor immune effects like interferon signaling after both X-, proton- and carbon-ion-irradiation; additionally, interferon induction is strongly dependent on LET in he tested cell lines; the survival of glioblastoma cells is reduced in a dose and LET-dependent manner; the glioblastoma-microglia crosstalk interferes with tumour progression and resistance to treatment and can modulate the therapeutic outcome; the “omics” profile were determined for selected conditions. The website developed for DORADIOS [https://www.doradios.dfvm.nipne.ro/] allows both researchers and the general public access to the most important information concerning the outputs of the project.
The fulfilment of all the targets we mentioned before lead to: an optimized preclinical model for glioblastoma treatment that could be validated in the next future projects by expanding the research to other glioblastoma stem cells models and organoids derived from patients and to in vivo experiments; the reveling of new effective combination treatments for glioma and new molecular mechanisms and identifying biomarker signatures that may support the development of personalized treatment of glioma patients. Furthermore, important new knowledge about differences in radiobiological responses for X-ray, protons and carbon-ions were obtained. In addition: the capacities of both partners (Romanian and Norwegian) to provide higher Technology Readiness level results for cancer drug market were increased; the research capability for Romanian team based on know-how transfer from the Norwegian team was increased; the Norwegian radiobiology researchers were prepared for future research exploiting the new proton radiotherapy centre at OUH (to be opened in 2025); the scientific connections of both teams was strengthen and enlarged, providing a real basis for future collaborative projects in the frame of European programs. We ultimately hope that on long term the validated preclinical model will be transferred to the pharmaceutical industry and to the clinics.
Summary of bilateral results
Given the common research direction of the consortium partners and the complementarity of the molecular biology techniques used, the current project represented the initiation of a longterm collaboration between the partners IFIN-HH and OUH. We maintained a close collaboration during the project. We submitted four joint papers to be published in international journal and we still have in preparation two more joint papers. Moreover, the multidisciplinary approach of this project will have impact beyond the two main partners involved through dissemination and project progress and activities with the associated collaborators (CEA and DMU). The success of this project consolidated/developed long-term collaborations on biological effects of hadrontherapy/X-ray radiotherapy in combination with drugs in the treatment of radioresistant glioblastoma in the frame of EU framework calls (i.e EURATOM Programme at topic Medical Application) starting from the actual consortium formula. CEA and IFIN-HH are already members of the Infrastructure Nationale (France and Romania) Hadron. CEA is also a founding member of ARCHADE (Advanced Resource Center for HADrontherapy) association. OUH will use the results for future research exploiting the new proton radiotherapy centre at OUH (to be opened in 2025). All the consortium members initiated and /or are part of several European Union grants. The agreements were done during this project to assure the traceability of the protocols used by each partner and will provide a solid basis to enlarge such type of approach by attracting other European laboratories in this collaboration enhancing the chances not only to get new results, but also to produce highly reproducible data and information necessary to standardize the protocols.