Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - GLINT (GlucoCEST Imaging of Neoplastic Tumours)

Teaser

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...

Summary

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 GLINT proposal, we aim 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), and 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. GlucoCEST achieves this using radio waves to magnetically label glucose in the body. This method therefore uses an injection of normal sugar and could offer a cheap, safe alternative to existing methods for detecting tumours, which require the injection of radioactive material.
The development and commercialisation of GlucoCEST MRI as an innovative in vivo new metabolic imaging technique through the GLINT consortium will:
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.
The GlucoCEST Imaging of Neoplastic Tumours (GLINT) consortium aims to bring the combination of native glucose and a non-metabolizable glucose derivative (3-O-methyl-glucose) as a combined examination to clinical oncology practice to assess cancer glucose uptake and metabolism, thereby providing a wide-ranging new diagnostic tool for one of the most devastating diseases in the world. A major deliverable of GLINT is therefore to provide a cheap, widely available, more comprehensive, non-invasive, radiation-free complementary method to nuclear medicine techniques currently used for cancer assessment.

Work performed

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: For glucoCEST a robust dynamic imaging is needed, as well as a presaturation with minimal direct water saturation. To achieve this, we developed a snapshot CEST MRI method, consisting of a novel adiabatic spin-lock preparation phase and a fast 3D snapshot readout.

WP3: Using the modelling and analysis of compartmental models for different types of glucose uptake in the body, a CEST data processing software using Olea Sphere® Software Development Kit (SDK) was designed and implemented to process glucoCEST, APT and Iopamidol-CEST data. The software performance was tested on data provided by GLINT partners.

WP4: In order to separately assess glucose uptake and metabolism, both native and methylated glucose were measured together with a clear delineation of the in vivo characteristics of the metabolic pathway. The rate of mutarotation was found to be very long up to several days at low temperatures. The anomeric ratio at equilibrium was estimated to determine the pH in tumours, showing low to moderate/high correlation between the two image-based metrics in different regions of the tumours.

WP5: 3OMG was tested to detect tumours in several breast cancer models of murine and human origin, for different routes of administration of 3OMG and to compare the method with glucoCEST and with 18FDG‐PET on the same animals. In vitro D-Glucose provides higher CEST contrast at lower pH values, whereas 3OMG provides higher CEST contrast at pH 7.0-7.4 independent from B1 saturation power level. At 7T and 37°C, the detection threshold was found to be ca. 5 mM for 1 µT B1 and intravenous administration with 1.5 g/Kg produced enough detectable glucoCEST contrast in vivo.

WP6: A GMP-like batch was released to BCO in December 2017 and the first part of nonclinical safety studies reports has been concluded. Moreover, requests for ethical approval for GLP pharmacokinetics, biodistribution and excretion studies in rodents have been submitted to Italian Ministry of Health on 13 December, 2018.

WP7: Positive signal was observed only in brain of four patients, but not in three adult lymphoma patients and one prostate cancer patient. It was found that the signal-to-noise ratio is not high enough to obtain a signal outside the brain possibly due to lower glucose delivery and outside cancer types with large vascular components.

WP8: During the second period, WP8 carried out scientific and non-scientific dissemination activities at international meetings and events. The project’s knowledge management strategy was fully implemented and steps were taken for the protection of newly generated knowledge. Moreover, efforts to monitor the scientific findings to identify marketable results continued and preparations started for the development of a final exploitation strategy for GLINT (D8.4).

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.

Final results

• A new data acquisition technique (snap-shot CEST) was developed and applied to volunteers and patient.
• 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.

Website & more info

More info: http://www.glint-project.eu.