Isocitrate dehydrogenase IDH1 and IDH2 are metabolic enzymes that catalyze the conversion of isocitrate to ?-ketoglutarate (?-KG) in cells. Genes encoding for IDH1 and IDH2 are mutated in >70% of grade II and III gliomas and secondary glioblastomas. They are also present in a variety of non-CNS tumors with varying frequencies. Mutant IDH1/2 lose their normal catalytic activity but gain the ability to convert ?-KG to 2-hydroxyglutarate (2-HG). 2-HG has a structure similar to ?-KG and competitively inhibits several of the ?-KG-dependent dioxygenases in cells, thereby, playing a role in tumor initiation. IDH mutations are the earliest genetic changes in the formation of low-grade gliomas. On the other hand, glioma patients with IDH1/2 mutations are found to have significantly longer survival compared to those with normal IDH1 tumors, suggesting the use of these mutations as prognostic biomarkers. IDH mutations are analyzed by ex vivo procedures and currently, there is no clinically applicable method available for noninvasive detection of these mutations in cancers.
We aim to develop a positron emission tomography (PET) imaging method using radiolabeled probes to image IDH1 mutations, with the goal of addressing the critical need for an imaging biomarker to study these cancer-associated mutations. Our preliminary studies demonstrate the feasibility of developing radiotracers for the most commonly occurring IDH1 mutation, IDH1-R132H, using small-molecule inhibitors of the mutant enzyme. In this project, we will synthesize nonradioactive analogs for several candidate radiotracers and examine their inhibitory potency against the purified mutant enzyme IDH1-R132H in vitro. These experiments will establish the potential of these analogs to bind to the mutant IDH1 and will enable selection of compounds for radiolabeling experiments in Specific Aim 2.
In Specific Aim 2, we will synthesize radiolabeled compounds starting from appropriate precursors and fluorine-18 and/or radioiodine. The uptake and retention of radiotracers in mutant IDH1-expressing cells will be examined using glioma cell lines having native IDH1-R132H mutations or stably-expressing the mutant enzyme (R132H). The specificity will be verified in parallel experiments using isogenic cell lines carrying wild-type IDH1.
Specific Aim 3 will expand into in vivo evaluation and will investigate the biological characteristics and tumor localization properties of promising radiotracers. Biodistribution studies will be conducted initially in normal mice to study normal tissue distribution characteristics. This will be followed by studies in athymic mice carrying mutant IDH1 tumor xenografts to investigate the in vivo binding and retention of radiotracers in tumors. Finally, small-animal PET studies will be conducted using clinically relevant orthotopic tumor models (R132H) to demonstrate the feasibility of imaging IDH1 mutations in vivo. The information obtained from these studies will help in developing a method for PET imaging of IDH1 mutations with potential for clinical translation.
Isocitrate dehydrogenase IDH1 and IDH2 are metabolic enzymes that catalyze the conversion of isocitrate to alpha-ketoglutarate in cells. Genes encoding for IDH enzymes are mutated frequently in brain tumors and many other types of cancers, and are thought to be responsible for the initiation of these tumors. In this project, we will develop radiolabeled compounds that specifically bind to the mutant form of the IDH1 enzyme, with the goal of utilizing these compounds for the noninvasive detection of IDH mutations in cancer patients using positron emission tomography (PET) imaging.
|Chitneni, Satish K; Reitman, Zachary J; Gooden, David M et al. (2016) Radiolabeled inhibitors as probes for imaging mutant IDH1 expression in gliomas: Synthesis and preliminary evaluation of labeled butyl-phenyl sulfonamide analogs. Eur J Med Chem 119:218-30|
|Chitneni, Satish K (2016) IDH1 Mutations in Glioma: Considerations for Radiotracer Development. SM Radiol J 2:|