Development of PET radioligands for imaging of mutant Isocitrate Dehydrogenase 1 (mIDH1) in solid tumours.

• Applicants: Dr. Winnie Deuther-Conrad; Professor Dr. Tareq Juratli
• Subject Area: Radiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530200781

Gliomas and chondrosarcomas are highly invasive and infiltrative solid tumours that pose significant clinical challenges in terms of complete surgical resection. These tumours often harbor mutated isocitrate dehydrogenase enzymes (mIDH), making them attractive therapeutic targets. Thus, accurate evaluation of mIDH status is essential for effective patient management. Currently, the presence of mIDH1 is determined either by invasive biopsy or indirectly by measuring the mIDH-derived oncometabolite 2-hydroxyglutarate (2-HG) using magnetic resonance spectroscopy (MRS). Here, we propose a novel approach to develop non-invasive imaging tools for the detection of the mIDH1 protein using positron emission tomography (PET) to facilitate targeted therapy. To achieve this, we aim to develop radiofluorinated or radioiodinated ligands using medicinal chemistry, based on mIDH inhibitors that are currently under investigation in clinical trials. As a novel approach, we will perform potency and affinity studies with wild-type and mutant enzymes to test a correlation between functional compound selectivity and selective binding. Furthermore, we will investigate radioligand suitability through cell uptake studies and binding studies performed with lysates from patient-derived mIDH-positive cancer cells. We will further investigate in vivo the mIDH1-targeted radioligands, fulfilling pre-defined criteria in vitro, regarding pharmacokinetics, complementary metabolite studies, and tumour uptake by dynamic imaging in naïve animals and tumour xenograft models. Additionally, mIDH-positive glioma obtained directly from mIDH-glioma patients will be used to establish PDX models, which will be utilized to perform PET scans to detect the mIDH1 protein using the newly developed radioligands and will be directly compared with the results of 2HG-MRS. Overall, the development of these novel imaging tools may improve the selection of cancer patients who are most likely to benefit from precision medicine using a targeted therapy. By offering a non-invasive method for determining the mIDH1 status, these radioligands can aid in the accurate diagnosis and monitoring of patients with glioma and CHS.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Professorin Dr. Aurelie Maisonial-Bessett