3D 2HG mapping as biomarker for IDH-mutation in glioma

The association of WHO grade II and III gliomas and secondary glioblastomas with mutations in the IDH1/2 enzymes is a recent but important discovery as these mutations are an indicator for longer overall patient survival. Both IDH mutations affect the tumour cell metabolism and cause the production of 2- hydroxyglutarate (2HG), making 2HG a specific biomarker for IDH and glioma. As a non-invasive alternative to biopsies, magnetic resonance spectroscopic imaging (MRSI) can be utilised, but is currently not ready for clinical practice, especially at ultra-high field systems. Challenges include spatial resolution, long measurement times, signal contamination and subject movement. We hypothesise to overcome these challenges by developing MRSI at 7 T into a robust method for non-invasive full brain 3D 2HG imaging and demonstrating the improvements over lower field strengths. Adding this sequence to standard glioma MR protocols will increase diagnostic accuracy for detection of IDH-mutation and improve treatment monitoring. This requires to identify the best-performing acquisition scheme and to implement spatial-spectral encoding, lipid contamination correction, a dedicated lipid crusher coil, improved B0-shimming and real-time motion correction. The benefits of the 7 T implementation over 3 T will be determined, while a co-developed 3 T version can be disseminated easier. A pilot study with a small patient population will identify the benefits of this 2HG-MRSI method regarding diagnosis and treatment monitoring.

Certain kinds of brain tumours, called gliomas, are difficult to treat and have a very low average patient survival time. Over the last years, science has found several mutations within these tumours that are important for the growth and energy supply of these tumours, but their effects are not yet fully understood. One of these mutations affects the enzyme isocitrate dehydrogenase (IDH) and is very common, meaning that it can be identified in most gliomas. The IDH mutation status (mutated or wildtype) has even been integrated in the official WHO classification of tumours of the central nervous system. The presence of IDH mutations increases the likelihood of a better patient outcome, possibly due to changes in the tumour biochemistry compared to other gliomas. One such change is the production of 2-hydroxyglutarate (2HG) by the mutated IDH instead of another molecule. While currently, IDH status can only be determined by genetic testing of tumour cells after a biopsy or surgical removal of the tumour, methods to determine it before treatment start are under development. One of these is the topic of this project. Using magnetic resonance imaging (MRI) devices, certain molecules can be measured noninvasively with a range of magnetic resonance spectroscopy (MRS) techniques. 2HG, which is only present in measurable concentrations in a few diseases and foremost IDH-mutated gliomas, is one of these. In this project, we aimed to improve the available methods in order to easier determine IDH status and to better identify active tumour regions, for example by the fast measurement of high-resolution MRS images of 2HG. In order to do this, we used Austria's only MRI scanner with a field strength of 7 Tesla. We did manage to improve our MRS techniques in relevant ways, but in the end could not achieve robust detection of 2HG. One factor was the COVID pandemic that limited our possibilities to acquire sufficient patient datasets for our study. We therefore used an alternative strategy and investigated the use of other molecules that were well-detectable in tumours by our method, such as glutamine. This was successful and we found that a classification software could identify the IDH status based on our MRS data alone very well (quantitatively summarised with an AUC > 0.85). We hope that with even more technical improvements of our 7 Tesla MRS and more patient data, even better classification is possible. The sooner IDH-status can be determined with clinical MRI, the better cancer treatment for gliomas can be improved and personalised. This will hopefully improve life expectancy and quality of live for brain tumour patients.