Fluorescence and Reactive oxygen Intermediates by Neutron Generated electronic Excitation as a foundation for radically new cancer therapies

Informations projet

FRINGE

N° de convention de subvention: 828922

DOI

10.3030/828922

Projet clôturé

Date de signature de la CE 18 Decembre 2018

Date de début 1 Mai 2019

Date de fin 31 Octobre 2024

Financé au titre de

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Coût total

€ 3 979 485,00

Contribution de l’UE

€ 3 979 485,00

Coordonné par

OSLO UNIVERSITETSSYKEHUS HF
Norway

Periodic Reporting for period 4 - FRINGE (Fluorescence and Reactive oxygen Intermediates by Neutron Generated electronic Excitation as a foundation for radically new cancer therapies)

Période du rapport: 2023-11-01 au 2024-10-31

Résumé du contexte et des objectifs généraux du projet

Deep lying tumours, such as the aggressive brain cancer glioblastoma multiforme (GBM) remain very difficult to treat and existing therapies offer only marginal increase in survival rates. Photomedical therapies have shown to be very effective, but they remain mainly limited due to their insufficient depth of light penetration into tissue, not able to reach deep-lying tumours and cancer cells. Current neutron-based therapies on the other hand have sufficient penetration depth but are not precise enough to target specific forms of cancer.
The relative survival rate for adults diagnosed with GBM is less than 30% within one year of diagnosis, and only 3% of patients live longer than five years after initial diagnosis. With over 28,000 new cases of malignant GBM diagnosed every year in the European Union (EU) and the 240,000 patients globally each year, research for new therapies is urgently needed.
The goal of the FRINGE project is to lay the foundation for a new treatment, proposing a genuinely new neutron-activated technology. The project aims to provide proof-of-principle for this future technology. At its heart are chemical agents, photosensitisers normally used in photomedical therapies activated by light, that will accumulate in the tumours especially in brain cancers where the blood brain barrier is compromised. The photosensitisers designed for FRINGE will contain metal centres like Gadolinium (Gd) to enable interaction with incoming neutrons and facilitate the transfer of neutron energy into electron excitation and of the chemical agent, similarly to what happens with light. The interaction of the FRINGE compounds with ambient oxygen will then generate reactive oxygen species that will kill the tumour cells from the inside.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Selected compounds of the library prepared by our synthetic partners were tested in solutions and gels during this reporting period. The IFE spectrograph at PSI was utilised to register fluorescence both at the NEUTRA and ICON instruments. We were unable to register fluorescence even when the old OUS spectrograph system was shipped to PSI from Norway. We then focused on the detection of singlet oxygen from solutions. We did that using PpIX as an indirect sensor through the formation of its singlet-oxygen-dependent photoproduct PppIX. While PpIX generated singlet oxygen on its own, KTH 2:7 greatly enhanced this production. This was observed only upon irradiation at the CVŘež and NEUTRA (PSI) facilities which produced thermal and some fast neutrons, but not at ICON (PSI) where predominantly cold neutrons were produced. These studies were augmented with the use of singlet oxygen scavengers like DABCO. Detection using singlet oxygen probes failed, as some of these interacted directly with the neutron beam while others were too insensitive to register singlet oxygen. The solution work was complemented with cell work at CVŘež on various GBM cell lines. KTH 2:7 gave cytotoxic results following neutron irradiation on many occasions while, PpIX also gave results in some cases, even though it does not bear a Gd metal. KTH 4:30 where GD is chelated in a DOTA outside the porphyrin core as well as chelated Gd (DOTA and DTPA) did not give any cytotoxic results following neutron irradiation in any occasion. Next, the FRINGE animal experiments were prepared with tumour establishment, toxicity and biodistribution studies at OUS. The animal-work accreditation of the reactor at CVŘež was approved in August 2023, while the application for FRINGE animal experiments at CVŘež was approved by the authorities. A biological hub was established at CVŘež with the facilities to perform work on cells while CVŘež were subcontracted for their services and our colleagues from Charles University Prague engaged via an in-kind contribution against payment for support on the cell and animal work. The CVŘež reactor port HK-1 was reconfigured for the animal studies which started in February 2024 and concluded at the end of October 2025. These studies were performed on two models, one mouse tumour model (C57BL6 mice/ GL261 cells) and one human tumour model (NOD-SCID-γ mice/ u87 cells). The results of the animal studies are promising in the NOD-SCID-γ mice showing a tumour growth inhibition following the FRINGE treatment, while in the C57BL6 mice, no conclusion could be made due to the innate immunity and self-healing effect.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The main impact of FRINGE will be to establish the proof-of-principle for a radically new cancer therapy which will work in conjunction with neutron capture therapy, with the potential to become the future gold standard for treating deep lying cancers, and profoundly increasing the overall survival and quality of life of cancer patients. The project will show that it is possible to design novel photosensitisers (PS) that can be electronically excited by neutrons and to achieve a transfer of a sufficiently high fraction of the neutron energy to the PS, as well as to yield a sufficiently high amount of reactive oxygen species (ROS) to kill tumour cells.
FRINGE has produced promising results both in cell and animal models. Now that the proof of principle has been established, there is a need to elucidate the mechanisms behind FRINGE, to optimise it and transform it into a potent clinical modality. So far the project has greatly contributed to science by unearthing another effect never encountered before, while it has provided work and training for several young researchers, who also had the opportunity to work on a FET Open project. Also, the project has provided partners the opportunity to expand their collaborations and form some great teams that have already formed consortia for funded follow-up projects. Finally from a management and coordination point of view, FRINGE has trained us to successfully mitigate several simultaneous force-majeure situations, which could have proven catastrophic to the project

The FRINGE concept