Amino acid PET tracers are reliable markers of treatment responses to single-agent or combination therapies including temozolomide, interferon-β, and/or bevacizumab for glioblastoma

Ono, Takahiro; Sasajima, Toshio; Doi, Yoshihiro; Oka, Shuntaro; Ono, Masahiro; Kanagawa, Masaru; Baden, Atsumi; Mizoi, Kazuo; Shimizu, Hiroaki

doi:10.1016/j.nucmedbio.2015.01.008

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…The results of the present study are in line with those of a previous study using the amino acid tracer 3 H-MET and the artificial amino acid trans-1-amino-3-fluoro-1-14 C-cyclobutanecarboxylic acid in the U87 tumor model (30). Therefore, the present study confirms the previous experimental and clinical finding that PET using 18 F-FET and other amino acid tracers is able to disclose the phenomenon of pseudoprogression, which is a frequent diagnostic problem in conventional MRI during antiangiogenic therapy.…”

Section: Discussionsupporting

confidence: 92%

“…Several experimental studies have already examined the usefulness of different PET tracers for monitoring antiangiogenic therapy (30). Beyond radiolabeled amino acids, the proliferation tracer 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT) has been investigated in 2 clinical trials (41,42).…”

Section: Discussionmentioning

confidence: 99%

“…In this preclinical study, the influence of antiangiogenic treatment with bevacizumab on BBB integrity, 18 F-FET uptake, and the slope of the late phase of the time-activity curve was tested in a U87 human glioblastoma xenograft model. This tumor model was chosen because it is largely resistant to bevacizumab on the one hand but shows a significant decrease in contrast enhancement on MRI after bevacizumab treatment on the other hand (29,30). Therefore, it appears to be well suited for simulating the phenomenon of the pseudoresponse and for testing the role of 18 F-FET PET in this setting.…”

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confidence: 99%

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Influence of Bevacizumab on Blood–Brain Barrier Permeability and O-(2-¹⁸F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas

et al. 2017

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Restoration of the blood-brain barrier (BBB) after antiangiogenic therapy of gliomas with bevacizumab may result in a decrease in contrast enhancement on MRI despite tumor progression. This so-called pseudoresponse is difficult to differentiate from a true tumor response with conventional MRI. Initial patient studies have indicated that PET using -(2-F-fluoroethyl)-l-tyrosine (F-FET) may be helpful for solving this diagnostic problem. This study was performed to investigate the effects of bevacizumab on BBB permeability and F-FET uptake in a human xenograft model. Human U87 glioblastoma cells were implanted into the striatum of immunodeficient RNU rats. F-FET PET scans and ex vivo autoradiography were performed in animals receiving a single high dose of bevacizumab (45 mg/kg 2 d before PET; = 9) or in animals receiving 2 lower doses (10 mg/kg 9 and 2 d before PET; = 10) to evaluate short-term and long-term effects on the BBB, respectively, and in control animals without bevacizumab treatment ( = 8). Time-activity curves, slope, and tumor-to-brain ratios of F-FET uptake (18-61 min after injection) were evaluated using a volume-of-interest analysis. After PET scanning, Evans blue dye (EBD) was injected into animals, and cryosections of the brains were evaluated by autoradiography, by histology, and for EBD fluorescence to assess BBB permeability. Compared with the control, short-term bevacizumab therapy resulted in a trend toward BBB restoration ( = 0.055) and long-term therapy resulted in a significant decrease ( = 0.004) in BBB permeability, as assessed by EBD fluorescence. In contrast, no significant differences in tumor-to-brain ratios or slope of F-FET uptake were observed in PET and autoradiography ( > 0.05). F-FET uptake in glioblastomas seems to be largely independent of BBB permeability and reflects the viability of tumor tissue during antiangiogenic therapy more reliably than contrast-enhanced MRI.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Influence of Bevacizumab on Blood–Brain Barrier Permeability and O-(2-¹⁸F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas

et al. 2017

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“…In orthotopic murine models of GBM treated with antiangiogenic drugs, the tumor cells invade perivascular spaces and form satellites separated from the primary tumor . To investigate the effects of bevacizumab in vivo , the U87MG brain xenograft model has widely been used because it simulates the human condition showing a significant decrease in contrast enhancement on MRI . Reportedly, bevacizumab inhibits tumor growth and prolongs survival of U87 brain xenografts .…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma endothelium drives bevacizumab‐induced infiltrative growth via modulation of PLXDC1

Falchetti

D’Alessandris

Pacioni

et al. 2018

Intl Journal of Cancer

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Bevacizumab, a VEGF‐targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p = 0.0055; Student t‐test), however, bands of tumor cells spread through the brain farther than controls (p < 0.001; Student t‐test). Infiltrating tumor Cells exhibited tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over‐expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient‐derived glioma stem‐like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab‐treated rats. Our study indicates that bevacizumab‐induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells.

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“…The changes observed by amino acid PET [106][107][108][109] indicate deactivation of amino acid transport as an early sign of response to chemotherapy. FET-PET was more efficient (sensitivity 80%, specificity close to 100%) [110] than MRI in showing effects of multimodal treatment [111,112] Early changes of FET uptake of > 10% after postoperative radiochemotherapy predicted a significantly longer disease-free and overall survival in patients with glioblastomas [113].…”

Section: Monitoring Treatment Effectsmentioning

confidence: 99%

Contribution of PET Imaging to Clinical Management of Gliomas

Heiss¹

2018

obm neurobiol

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Gliomas originating from glial cells comprise about 30% of all primary central nervous system tumors and 80% of malignant brain tumors. Gliomas differ in their biological activity and are categorized according to grades, from benign to malignant with high recurrence rates. For diagnosis, location and extent of the tumor is assessed by CT and MRI, but for grading, additional parameters are necessary: contrast enhanced CT and MRI reveal damage of the blood-brain barrier, perfusion-weighted MRI shows regional blood supply, and MR spectroscopy permits insight into regional metabolism. Positron emission tomography (PET) of glucose metabolism as well as amino acid and nucleoside uptake can assess tumor grade and invasive growth, indicate effects on function of tissues outside of the tumor, demonstrate treatment efficacy, detect recurrences, and yield prognostic information. Coregistration of PET and MRI combines high-resolution morphological information with biological information. This imaging technology is optimized in hybrid MRI/PET by which morphologic, functional, metabolic, and molecular information is assessed simultaneously in the human brain.

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Amino acid PET tracers are reliable markers of treatment responses to single-agent or combination therapies including temozolomide, interferon-β, and/or bevacizumab for glioblastoma

Cited by 15 publications

References 36 publications

Influence of Bevacizumab on Blood–Brain Barrier Permeability and O-(2-¹⁸F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas

Influence of Bevacizumab on Blood–Brain Barrier Permeability and O-(2-¹⁸F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas

Glioblastoma endothelium drives bevacizumab‐induced infiltrative growth via modulation of PLXDC1

Contribution of PET Imaging to Clinical Management of Gliomas

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Amino acid PET tracers are reliable markers of treatment responses to single-agent or combination therapies including temozolomide, interferon-β, and/or bevacizumab for glioblastoma

Cited by 15 publications

References 36 publications

Influence of Bevacizumab on Blood–Brain Barrier Permeability and O-(2-18F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas

Influence of Bevacizumab on Blood–Brain Barrier Permeability and O-(2-18F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas

Glioblastoma endothelium drives bevacizumab‐induced infiltrative growth via modulation of PLXDC1

Contribution of PET Imaging to Clinical Management of Gliomas

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Product

Resources

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Influence of Bevacizumab on Blood–Brain Barrier Permeability and O-(2-¹⁸F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas

Influence of Bevacizumab on Blood–Brain Barrier Permeability and O-(2-¹⁸F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas