Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [18F]fluoromethyl-(1,2-2H4)-choline

Dubash, Suraiya; Inglese, Marianna; Mauri, Francesco; Kozlowski, Kasia; Trivedi, Pritesh; Arshad, Mubarik; Challapalli, Amarnath; Barwick, Tara; Al-Nahhas, Adil; Stanbridge, Rex; Lewanski, Conrad; Berry, Matthew; Bowen, Frances; Aboagye, Eric O.

doi:10.7150/thno.47298

Cited by 11 publications

(16 citation statements)

References 41 publications

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“…We performed [ 18 F]-D4-FCH dynamic PET scans in mice to gain an understanding of the tumour kinetics and modulation by ABC transporters. Given that the human dynamic scans for this radiotracer are reported in lung cancer [ 14 ], the ABCB4-rich PC-9 human non-small cell lung cancer (NSCLC) xenograft model was used [ 44 ]. Mice were treated with a clinically approved drug in this setting, the epidermal growth factor receptor antagonist (EGFR) gefitinib.…”

Section: Resultsmentioning

confidence: 99%

“…The recently reported dynamic PET data from the NSCLC patients ( n = 17) scanned with 18 F-D4-FCH were reassessed to investigate the efflux of the [ 18 F]-D4-FCH kinetics [ 14 ]. The pretherapy ~1 h dynamic [ 18 F]-D4-FCH PET/CT scans (maximum dose of 370 MBq) were analysed with graphical and compartmental methods.…”

Section: Resultsmentioning

confidence: 99%

“…The study cohort was reported recently [ 12 ] and included seventeen patients (mean age ± SD were 64 ± 11 y; age range 39–84 y; weight ± SD, 68.9 ± 15 kg; weight range, 49.7–93.3 kg) with confirmed NSCLC who underwent [ 18 F]-D4-FCH PET/CT [ 14 ]. The parent plasma input function was generated by normalisation to the plasma-over-blood ratio and correcting for metabolites.…”

Section: Methodsmentioning

confidence: 99%

“…When PET scans with radiolabelled choline tracers, including [ 11 C]choline, are conducted dynamically over time, however, almost all tumours exhibit a rapid radiotracer uptake phase followed by a nearly unchanged time versus radioactivity (TAC) curve, regardless of their stability in oxidation [ 12 , 13 ]. This suggests that other mechanisms may influence the tumour radiolabelled choline biodistribution dynamics [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Using [ 18 F]-D4-FCH as an exemplar choline radiotracer (from its availability within our lab, representativeness for choline phosphorylation and to avoid a confound of oxidation), the aim of our study was to investigate how hypoxia or HIF-1α regulates the choline radiotracer dynamics and extend the findings to an understanding of the dynamics of radiolabelled choline localisation in mouse xenografts and human NSCLC recently reported by Dubash et al [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics

Inglese

Dubash

et al. 2021

Pharmaceutics

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Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore, may confound the uptake of choline radiotracer [18F]fluoromethyl-[1,2-2H4]-choline ([18F]-D4-FCH). The aim of this study was to investigate how hypoxia affects the choline radiotracer dynamics. Three underlying mechanisms by which hypoxia could potentially alter the uptake of the choline radiotracer, [18F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and the efflux of [18F]-D4-FCH and its phosphorylated product [18F]-D4-FCHP. The effects of hypoxia on [18F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer MDA-MB-231 cells. The mechanisms of radiotracer efflux were assessed by the cell uptake and immunofluorescence in vitro and examined in vivo (n = 24). The mathematical modelling methodology was further developed to verify the efflux hypothesis using [18F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (n = 17). We report a novel finding involving the export of phosphorylated [18F]-D4-FCH and [18F]-D4-FCHP via HIF-1α-responsive efflux transporters, including ABCB4, when the HIF-1α level is augmented. This is supported by a graphical analysis of human data with a compartmental model (M2T6k + k5) that accounts for the efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting the consideration of efflux in the modelling of radiotracer dynamics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics

Inglese

Dubash

et al. 2021

Pharmaceutics

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Optimising hypoxia PET imaging and its applications in guiding targeted radiation therapy for non‐small cell lung cancer: a scoping review

Marks,

Leech

2024

J of Medical Radiation Sci

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IntroductionNon‐small cell lung cancer (NSCLC) is the leading cause of cancer‐related death. Definitive treatment includes chemotherapy and radiation therapy. Tumour hypoxia impacts the efficacy of these treatment modalities. Novel positron‐emission tomography (PET) imaging has been developed to non‐invasively quantify hypoxic tumour subregions, and to guide personalised treatment strategies. This review evaluates the reliability of hypoxia imaging in NSCLC in relation to various tracers, its correlations to treatment‐related outcomes, and to assess if this imaging modality can be meaningfully applied into radiation therapy workflows.MethodsA literature search was conducted on the Medline (Ovid) and Embase databases. Searches included terms related to ‘hypoxia’, ‘positron‐emission tomography’, ‘magnetic resonance imaging’ and ‘lung cancer’. Results were filtered to exclude studies prior to 2011, and animal studies were excluded. Only studies referring to a confirmed pathology of NSCLC were included, while disease staging was not a limiting factor. Full‐text English language and translated literature examined included clinical trials, clinical cohort studies and feasibility studies.ResultsQuantification of hypoxic volumes in a pre‐treatment setting is of prognostic value, and indicative of treatment response. Dosimetric comparisons have highlighted potential to significantly dose escalate to hypoxic volumes without risk of additional toxicity. However, clinical data to support these strategies are lacking.ConclusionHeterogenous study design and non‐standardised imaging parameters have led to a lack of clarity regarding the application of hypoxia PET imaging in NSCLC. PET imaging using nitroimidazole tracers is the most investigated method of non‐invasively measuring tumour hypoxia and has potential to guide hypoxia‐targeted radiation therapy. Further clinical research is required to elucidate the benefits versus risks of dose‐escalation strategies.

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