Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas

Bosnyák, Edit; Kamson, David Olayinka; Guastella, Anthony R.; Varadarajan, Kaushik; Robinette, Natasha; Kupsky, William J.; Muzik, Otto; Michelhaugh, Sharon K.; Mittal, Sandeep; Juhász, Csaba

doi:10.1093/neuonc/nov098

Cited by 37 publications

(43 citation statements)

References 49 publications

(62 reference statements)

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“…Nevertheless, the high 18 F-FETrp uptake in the bladder and pancreas suggests that this tracer would not allow visualization of tumors in these organs because of high background activity. Despite the differences in distribution, both tracers demonstrated similarly low and continuous brain accumulation, suggesting that 18 F-FETrp will be suitable for the imaging of intracranial brain tumors as previously established with 11 C-AMT (18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Section: Radiation Dosimetry For 18 F-fetrpmentioning

confidence: 79%

“…The total injected activity in mice for the 18 F-FETrp tracer was between 5.5 and 9.2 MBq (150-250 mCi), a dose commonly used in smallanimal PET studies of mice using 18 F-labeled PET tracers (39,40). Because of the shorter half-life of the 11 C isotope (20 min), a higher activity was administered in the AMT study (20)(21)(22) MBq equivalent to 550-600 mCi). This dose was previously determined by our group as sufficient to obtain high-quality images in the PDX tumor models (35).…”

Section: Small-animal Pet/ctmentioning

confidence: 99%

“…11 C-AMT PET was originally designed to estimate brain serotonin synthesis in the context of neuropsychiatric disorders (15,16) but also demonstrated the ability to identify epileptic foci, epileptogenic tumors, and malformations (17,18). 11 C-AMT PET studies were further extended to nonepileptogenic primary and metastatic brain tumors (19)(20)(21)(22). These studies demonstrated variably high 11 C-AMT uptake in gliomas (18,23,24) and meningiomas (21) and showed strong prognostic value for survival in patients with recurrent glioblastoma (20).…”

mentioning

confidence: 99%

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Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

et al. 2016

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Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. a-11 C-methyl-L-tryptophan ( 11 C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of 11 C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-18 F-fluoroethyl)-L-tryptophan ( 18 F-FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway. In this study, we tested in vivo organ and tumor uptake and kinetics of 18 F-FETrp in patient-derived xenograft mouse models and compared them with 11 C-AMT uptake. Methods: Xenograft mouse models of glioblastoma and metastatic brain tumors (from lung and breast cancer) were developed by subcutaneous implantation of patient tumor fragments. Dynamic PET scans with 18 F-FETrp and 11 C-AMT were obtained for mice bearing human brain tumors 1-7 d apart. The biodistribution and tumoral SUVs for both tracers were compared. Results: 18 F-FETrp showed prominent uptake in the pancreas and no bone uptake, whereas 11 C-AMT showed higher uptake in the kidneys. Both tracers showed uptake in the xenograft tumors, with a plateau of approximately 30 min after injection; however, 18 F-FETrp showed higher tumoral SUV than 11 C-AMT in all 3 tumor types tested. The radiation dosimetry for 18 F-FETrp determined from the mouse data compared favorably with the clinical 18 F-FDG PET tracer. Conclusion: 18 F-FETrp tumoral uptake, biodistribution, and radiation dosimetry data provide strong preclinical evidence that this new radiotracer warrants further studies that may lead to a broadly applicable molecular imaging tool to examine abnormal tryptophan metabolism in human tumors.

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Section: Radiation Dosimetry For 18 F-fetrpmentioning

confidence: 79%

Section: Small-animal Pet/ctmentioning

confidence: 99%

mentioning

confidence: 99%

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Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

et al. 2016

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“…14 AMT-PET can detect and differentiate various primary and metastatic brain tumors, including glioblastomas. 15–17 We have also demonstrated that high tryptophan uptake in the suspected recurrence site was a strong prognostic imaging marker for 1-year and overall survival in patients with previously-treated glioblastoma independent of MRI and clinical prognostic factors. 18 However, PET findings were not correlated with molecular prognostic markers, and the potential prognostic value of AMT-PET in pre-treatment glioblastomas remained to be determined.…”

Section: Introductionmentioning

confidence: 76%

Prognostic Molecular and Imaging Biomarkers in Primary Glioblastoma

Bosnyák

Michelhaugh

Klinger

et al. 2017

Clinical Nuclear Medicine

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Purpose Several molecular glioma markers (including isocitrate dehydrogenase 1 [IDH1] mutation, amplification of the epidermal growth factor receptor [EGFR] and methylation of the O6-methylguanine-DNA methyltransferase [MGMT] promoter) have been associated with glioblastoma survival. In this study, we examined the association between tumoral amino acid uptake, molecular markers, and overall survival in patients with IDH1 wild-type (primary) glioblastoma. Materials and Methods Twenty-one patients with newly-diagnosed IDH1 wild-type glioblastomas underwent presurgical MRI and PET scanning with alpha[C-11]-L-methyl-tryptophan (AMT). MRI characteristics (T2 and T1 contrast volume), tumoral tryptophan uptake, PET-based metabolic tumor-volume and kinetic variables were correlated with prognostic molecular markers (EGFR and MGMT) and overall survival. Results EGFR amplification was associated with lower T1 contrast volume (P=.04) as well as lower T1-contrast/T2 volume (P=.04) and T1-contrast/PET volume ratios (P=.02). Tumors with MGMT promoter methylation showed lower metabolic volume (P=.045) and lower tumor/cortex AMT unidirectional uptake ratios than those with unmethylated MGMT promoter (P=.009). While neither EGFR amplification nor MGMT promoter methylation was significantly associated with survival, high AMT tumor/cortex uptake ratios on PET were strongly prognostic for longer survival (hazard ratio: 30; P=.002). Estimated mean overall survival was 26 months in patients with high vs. 8 months in those with low tumoral AMT uptake ratios. Conclusions The results demonstrate specific MRI and amino acid PET imaging characteristics associated with EGFR amplification and MGMT promoter methylation in patients with primary glioblastoma. High tryptophan uptake on PET may identify a subgroup with prolonged survival.

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“…Dynamic PET imaging provides information on the temporal characteristics of radiotracer distribution and allows PET tracer kinetic analysis for separation of tumoral tracer transport and trapping; for some tracers, the source of some of the trapped radioactivity is from metabolites. For example, in the case of the tryptophan derivative AMT, the tracer may undergo metabolism via the serotonin and also by the immunosuppressive kynurenine pathway [7, 9,16]; the latter is commonly upregulated in a variety of tumors, including gliomas, glioneuronal tumors and meningiomas [1,3,7,42]. AMT was shown to have a differential uptake in a variety of gliomas [13].…”

Section: Pet Imaging In Pretreatment Evaluation Of Pediatric Gliomasmentioning

confidence: 99%

PET and SPECT studies in children with hemispheric low-grade gliomas

Juhász

Bosnyák

2016

Childs Nerv Syst

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Molecular imaging is playing an increasing role in the pre-treatment evaluation of low-grade gliomas. While glucose positron emission tomography (PET) can be helpful to differentiate low-grade from high-grade tumors, PET imaging with amino acid radiotracers has several advantages, such as better differentiation between tumors and non-tumorous lesions, optimized biopsy targeting and improved detection of tumor recurrence. This review provides a brief overview of single photon emission computed tomography (SPECT) studies followed by a more detailed review of clinical applications of glucose and amino acid PET imaging in low-grade hemispheric gliomas. We discuss key differences in the performance of the most commonly utilized PET radiotracers and highlight the advantage of PET/MRI fusion to obtain optimal information about tumor extent, heterogeneity and metabolism. Recent data also suggest that simultaneous acquisition of PET/MR images and the combination of advanced MRI techniques with quantitative PET can further improve the pre- and post-treatment evaluation of pediatric brain tumors.

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Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas

Cited by 37 publications

References 49 publications

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

Prognostic Molecular and Imaging Biomarkers in Primary Glioblastoma

PET and SPECT studies in children with hemispheric low-grade gliomas

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Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas

Cited by 37 publications

References 49 publications

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

Prognostic Molecular and Imaging Biomarkers in Primary Glioblastoma

PET and SPECT studies in children with hemispheric low-grade gliomas

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Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts