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GlucoCEST Imaging of Neoplastic Tumours

Periodic Reporting for period 3 - GLINT (GlucoCEST Imaging of Neoplastic Tumours)

Reporting period: 2019-01-01 to 2019-12-31

Cancer as one of the most serious diseases accounts for 13% of all deaths worldwide and its early detection is vital to increase the chances of survival. Despite existing advanced medical imaging at present, there is a global lack of safe, cheap, easily accessible and accurate image-based evaluation technique to detect cancer. Within the GlucoCEST Imaging of Neoplastic Tumours (GLINT) proposal, we aimed to take advantage of the very high metabolism of cancer cells, which need a lot of sugar for their energy supply to be able to light it up using a new MRI method. This new technique is called ‘glucose chemical exchange saturation transfer’ (GlucoCEST). It is based on the sensitising of magnetic resonance imaging (MRI) scanners to glucose uptake, which caused tumours to appear as bright images on MR images.
Following a 4 year programme, the GLINT consortium concludes that:
1. The use of native glucose can be detected in patients, and provides a specific signature in glioma patients.
2. Several glucose analogues can also be detected and have shown promising results in preclinical settings.
3. A non-metabolizable glucose derivative (3-O-methyl-glucose), was tested and showed a good safety profile to be translated into the clinics. It also showed comparable imaging results as the gold standard FDG-PET.
WP1: WP1 ensured that an appropriate project management structure and governance, reflecting the project’s needs was set up in agreement with all partners. WP1 activities covered all aspects of project monitoring, reporting, financial and contractual administration in accordance with the Commission’s rules, ensuring proper communication within the consortium and implementing the project governance’s decisions.

WP2: Through WP2, numerous MRI methodologies were developed including advanced CEST readouts from 3T-9.4T robust adiabatic spin-lock pulses, and pTx CEST methods. Numerical quantification and optimization of glucoCEST MRI at 3T ,7T and 9.4T were performed and impact of motion artefacts in dynamic CEST imaging was assessed. This led to positive and reproducible results using GlucoCEST with adiabatic pulses and motion and dynamic B0 correction at 9.4T and 3T.

WP3: OM’s main output was to build a CEST data post-processing tool in Olea Sphere® to process CEST clinical and pre-clinical data of GLINT partners. Different plug-ins were delivered (APT, glucoCEST and Iopamidol-CEST). The performance and resilience of the SW solution was tested. The SW has been used in a clinical study conducted by UCL in glioma staging and IDH status detection. The results were divulged through a dedicated symposium on CEST imaging and through different publications/dissemination activities. The required documentation for commercialisation was compiled.

WP4: Within WP4, the potential biochemical pathways and the sources of the GlucoCEST signal for glucose analogues were assessed by exploring the uptake and metabolism of 3-O-Methyl-D-glucose (3OMG). Additionally, other glucose analogues such as glucosamine (GlcN), 2-O-Methyl-Dglucose (2OMG), and 6-deoxy-D-glucose (6DG) were tested. The 3OMG CEST MRI technology was found to be as effective as the FDG PET/CT method. The 13C NMR results together with in vivo CEST MRI suggest that the most pronounced CEST effect is achieved by GlcN metabolites.

WP5: WP5 aimed at characterizing the CEST contrast efficiency of glucose and 3OMG in different conditions and to assess their value as alternative to the FDG-PET technique. Different pH dependences were observed for glucose and 3OMG and CEST contrast detection was influenced by dosage, administration route and magnetic field strength, with contrast detectability at 3T requiring doses up to 3g/kg. A similar trend between GlucoCEST contrast and FDG-PET uptake was observed in murine tumour models with different glucose avidity and in some tumour models GlucoCEST contrast was more informative of the therapeutic response in comparison to FDG-PET.

WP6: The nonclinical safety pharmacology of 3OMG was evaluated in two in vivo studies in CD-1 mice. A safety pharmacology study (Irwin test) was aimed at the evaluation of the possible adverse effects of 3OMG on the Central Nervous System (CNS) and was performed according to Good Laboratory Practices (GLP). A supplemental safety pharmacology study in healthy mice aimed at evaluating the glycaemic levels following intravenous administration of 3OMG was also performed. The pharmacokinetics of 3OMG was evaluated in vivo. Plasma kinetics and distribution studies were performed in rats while elimination study was performed in mice. The toxicology of 3OMG was examined in two single-dose in vivo studies in rats, with a recovery period up to 14 days after dosing, one of them being in GLP.

WP7: WP7 aimed to characterise the CEST signal in three types of cancer with varying blood volume and expected metabolic rates (lymphoma, prostate cancer, glioma) at 3T. GlucoCEST protocols were established based on rapid assessment of B1+ and B0. Results showed that motion correction and B0 field inhomogeneity correction are crucial to avoid mistaking signal changes for a glucose response while field drift is a substantial contributor. After B0 field drift correction, glucoCEST signal were detected in all glioma patients with BBB breakdown whereas no significant glucoCEST signal enhancement was observed in tumour regions of patients with lymphoma and prostate cancer in vivo.

WP8: Several dissemination activities were carried out and GLINT was presented at major congresses and events as part of WP8. A project’s knowledge management strategy was developed and implemented. The project’s progress, its results and their potential impact and opportunities for exploitation were monitored. A detailed exploitation plan was developed, identifying the expected results and adequate exploitation routes, including dedicated business plans by the project’s industry partners.

WP9: This Work package was automatically generated by the European Commission’s online system to track the completion of the Ethics Requirements. Eighteen deliverable reports were completed to ensure that all the activities carried out in the GLINT project comply with ethical principles and relevant national, EU and international legislation.
The GLINT project has made the substantial progress on scientific, clinical and commercial aspects such as (among others):
• Novel CEST MRI acquisition techniques were developed and applied to patients.
• A software using Olea Sphere® Software Development Kit (SDK) was developed for CEST data processing.
• The first part of nonclinical safety studies reports has been concluded for a GMP-like batch of 3OMG
• The first-in-man studies in glioma (brain cancer) patients produced positive signal.

The development and commercialisation of GlucoCEST MRI as an innovative in vivo new metabolic imaging technique through the GLINT consortium are expected to:
• 1) enable personalised healthcare for cancer treatment by providing a cheap metabolic imaging alternative to improve patient selection
• 2) benefit the global cancer population by improving the diagnostic accuracy of MRI and providing early readouts of treatment efficacy, leading to improved clinical decisions and outcomes
• 3) reduce developmental costs of novel therapeutic molecules by providing more specific methods for patient selection and therapy monitoring.
Expected Outcomes of GLINT