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

Periodic Reporting for period 2 - FRINGE (Fluorescence and Reactive oxygen Intermediates by Neutron Generated electronic Excitation as a foundation for radically new cancer therapies)

Reporting period: 2020-11-01 to 2022-04-30

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.
The synthetic groups at Kappa Solutions AS (SYN, Norway) and the University of Chemistry and Technology Prague (VSCHT, Czech Republic) have prepared photosensitisers using inspiration from relevant literature, which have been photochemically characterized by UPV and also undergone neutron capture experiments at the Paul Scherrer Institute (PSI) near Zurich in Switzerland, CVŘež close to Prague in the Czech Republic and the tandem accelerator at NCSR Demokritos, Athens, Greece. These experiments have provided initial proof of principle of the FRINGE hypothesis in solutions and cell cultures, awaiting confirmation in the future runs. The synthetic work has been supported by extensive stability calculations provided by the University of Girona (Spain). OUS have additionally performed compound uptake and PDT studies on the compounds by SYN, finding very encouraging results by light activation of at least three compounds. At the National Centre for Scientific Research Demokritos (NCSRD, Greece) and the Institutt for Energiteknikk (IFE, Norway) pre-analysis calculations of the neutron irradiation experiments have been made to guide and model the experiments on solutions and biological samples. The optical detection systems have been installed at NCSRD and PSI, and the PSI instrument is being optimized by the manufacturer.
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 neuton 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 are able to 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.

If successful, FRINGE is expected to revolutionise the medical practice in oncology and neutron-based approaches in particular, which are currently in decline and the related infrastructure remains unused. Overall, the FRINGE consortium estimates that the therapy could enter clinical trials as soon as 5-10 years after the end of the project. The successful project will furthermore trigger new business options revolving around the commercialisation of new chemical agents and drugs, while another part will be developing new services, for example, by reactor or accelerator-based treatment centres and/or specialised medical services.
The FRINGE concept