PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Xin, Yangchun; Yue, Xuyi; Li, Hua; Li, Zhiqin; Cai, Hao; Choudhary, Arabinda K.; Zhang, Shaohui; Chugani, Diane C.; Langhans, Sigrid A.

doi:10.1038/s41598-020-60728-6

Cited by 7 publications

(5 citation statements)

References 52 publications

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“…The brain and heart-to-muscle ratios were significantly higher for FDG than L-[ 18 F]FETrp (n = 4, p < 0.05). The results are consistent with a high non-specific FDG uptake in the brain and heart [23]. Comparable results were observed in the liver-to-muscle ratio between the two radiotracers (Figure 3).…”

Section: Micropet Imagingsupporting

confidence: 87%

PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer

Yue,

Stauff,

Boyapati

et al. 2024

Pharmaceuticals

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Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high incidence of developing into malignant peripheral nerve sheath tumors (MPNSTs) with a 5-year survival rate of only 30%. Therefore, the accurate diagnosis and differentiation of MPNSTs from benign PNFs are critical to patient management. We studied a fluorine-18 labeled tryptophan positron emission tomography (PET) radiotracer, 1-(2-[18F]fluoroethyl)-L-tryptophan (L-[18F]FETrp), to detect NF1-associated tumors in an animal model. An ex vivo biodistribution study of L-[18F]FETrp showed a similar tracer distribution and kinetics between the wild-type and triple mutant mice with the highest uptake in the pancreas. Bone uptake was stable. Brain uptake was low during the 90-min uptake period. Static PET imaging at 60 min post-injection showed L-[18F]FETrp had a comparable tumor uptake with [1⁸F]fluorodeoxyglucose (FDG). However, L-[18F]FETrp showed a significantly higher tumor-to-brain ratio than FDG (n = 4, p < 0.05). Sixty-minute-long dynamic PET scans using the two radiotracers showed similar kidney, liver, and lung kinetics. A dysregulated tryptophan metabolism in NF1 mice was further confirmed using immunohistostaining. L-[18F]FETrp is warranted to further investigate differentiating malignant NF1 tumors from benign PNFs. The study may reveal the tryptophan–kynurenine pathway as a therapeutic target for treating NF1.

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Section: Micropet Imagingsupporting

confidence: 87%

PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer

Yue,

Stauff,

Boyapati

et al. 2024

Pharmaceuticals

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“…In amino acids-deprived conditions, mTOR activity is inhibited, which promotes autophagy-dependent catabolism, providing energy and supporting cell survival. Radiotracing experiments demonstrated that tryptophan is greedily metabolized in MB patients ( Xin et al, 2020 ) and its depletion from the tumor microenvironment is associated with the activity of tryptophan catabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1). mTORC1 inhibition by rapamycin treatment was able to increase IDO1 expression ( Folgiero et al, 2016 ), suggesting the existence of a crosstalk between tryptophan levels and mTOR in MB, which is critical for the effectiveness of mTOR targeting approaches.…”

Section: Metabolic Reprogramming In Medulloblastomamentioning

confidence: 99%

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Marabitti

Giansanti²,

Mitri³

et al. 2022

Front. Cell Dev. Biol.

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Tumor-specific alterations in metabolism have been recognized to sustain the production of ATP and macromolecules needed for cell growth, division and survival in many cancer types. However, metabolic heterogeneity poses a challenge for the establishment of effective anticancer therapies that exploit metabolic vulnerabilities. Medulloblastoma (MB) is one of the most heterogeneous malignant pediatric brain tumors, divided into four molecular subgroups (Wingless, Sonic Hedgehog, Group 3 and Group 4). Recent progresses in genomics, single-cell sequencing, and novel tumor models have updated the classification and stratification of MB, highlighting the complex intratumoral cellular diversity of this cancer. In this review, we emphasize the mechanisms through which MB cells rewire their metabolism and energy production networks to support and empower rapid growth, survival under stressful conditions, invasion, metastasis, and resistance to therapy. Additionally, we discuss the potential clinical benefits of currently available drugs that could target energy metabolism to suppress MB progression and increase the efficacy of the current MB therapies.

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“…The tryptophan and tyrosine uptake rates of MB over the ones in the healthy cerebellum were determined as 3.5–3.7 and 2.8, respectively [ 93 , 94 ]. Using these ratios and flux rates found in the healthy brain model [ 15 ], upper bounds of tryptophan and tyrosine uptakes were computed as 0.0074 mmol/gDW/h and 0.0028 mmol/gDW/h.…”

Section: Methodsmentioning

confidence: 99%

Identification of Therapeutic Targets for Medulloblastoma by Tissue-Specific Genome-Scale Metabolic Model

Ozbek

Ülgen

2023

Molecules

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Medulloblastoma (MB), occurring in the cerebellum, is the most common childhood brain tumor. Because conventional methods decline life quality and endanger children with detrimental side effects, computer models are needed to imitate the characteristics of cancer cells and uncover effective therapeutic targets with minimum toxic effects on healthy cells. In this study, metabolic changes specific to MB were captured by the genome-scale metabolic brain model integrated with transcriptome data. To determine the roles of sphingolipid metabolism in proliferation and metastasis in the cancer cell, 79 reactions were incorporated into the MB model. The pathways employed by MB without a carbon source and the link between metastasis and the Warburg effect were examined in detail. To reveal therapeutic targets for MB, biomass-coupled reactions, the essential genes/gene products, and the antimetabolites, which might deplete the use of metabolites in cells by triggering competitive inhibition, were determined. As a result, interfering with the enzymes associated with fatty acid synthesis (FAs) and the mevalonate pathway in cholesterol synthesis, suppressing cardiolipin production, and tumor-supporting sphingolipid metabolites might be effective therapeutic approaches for MB. Moreover, decreasing the activity of succinate synthesis and GABA-catalyzing enzymes concurrently might be a promising strategy for metastatic MB.

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PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Cited by 7 publications

References 52 publications

PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer

PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Identification of Therapeutic Targets for Medulloblastoma by Tissue-Specific Genome-Scale Metabolic Model

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