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Preclinical Applications of 3'-Deoxy-3'-[¹⁸F]Fluorothymidine in Oncology - A Systematic Review.

ABSTRACT: The positron emission tomography (PET) tracer 3'-deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT) has been proposed to measure cell proliferation non-invasively in vivo. Hence, it should provide valuable information for response assessment to tumor therapies. To date, [¹⁸F]FLT uptake has found limited use as a response biomarker in clinical trials in part because a better understanding is needed of the determinants of [¹⁸F]FLT uptake and therapy-induced changes of its retention in the tumor. In this systematic review of preclinical [¹⁸F]FLT studies, comprising 174 reports, we identify the factors governing [¹⁸F]FLT uptake in tumors, among which thymidine kinase 1 plays a primary role. The majority of publications (83 %) report that decreased [¹⁸F]FLT uptake reflects the effects of anticancer therapies. 144 times [¹⁸F]FLT uptake was related to changes in proliferation as determined by ex vivo analyses. Of these approaches, 77 % describe a positive relation, implying a good concordance of tracer accumulation and tumor biology. These preclinical data indicate that [¹⁸F]FLT uptake holds promise as an imaging biomarker for response assessment in clinical studies. Understanding of the parameters which influence cellular [¹⁸F]FLT uptake and retention as well as the mechanism of changes induced by therapy is essential for successful implementation of this PET tracer. Hence, our systematic review provides the background for the use of [¹⁸F]FLT in future clinical studies.

SUBMITTER: Schelhaas S

PROVIDER: S-EPMC5196884 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Preclinical Applications of 3'-Deoxy-3'-[18F]Fluorothymidine in Oncology - A Systematic Review.

Schelhaas Sonja S Heinzmann Kathrin K Bollineni Vikram R VR Kramer Gerbrand M GM Liu Yan Y Waterton John C JC Aboagye Eric O EO Shields Anthony F AF Soloviev Dmitry D Jacobs Andreas H AH

Theranostics 20170101 1

The positron emission tomography (PET) tracer 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been proposed to measure cell proliferation non-invasively in vivo. Hence, it should provide valuable information for response assessment to tumor therapies. To date, [18F]FLT uptake has found limited use as a response biomarker in clinical trials in part because a better understanding is needed of the determinants of [18F]FLT uptake and therapy-induced ...[more]

PMID: 28042315

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Project description:Selective inhibition of oncogenic targets and associated signaling pathways forms the basis of personalized cancer medicine. The clinical success of (V600E)BRAF inhibition in melanoma, coupled with the emergence of acquired resistance, underscores the importance of rigorously validating quantitative biomarkers of treatment response in this and similar settings. Because constitutive activation of BRAF leads to proliferation in tumors, we explored 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET to noninvasively quantify changes in tumor proliferation that are associated with pharmacologic inhibition of (V600E)BRAF downstream effectors and that precede changes in tumor volume.Human colorectal cancer (CRC) cell lines expressing (V600E)BRAF were used to explore relationships between upregulation of p27 and phosphorylation of BRAF downstream effectors on small-molecule (V600E)BRAF inhibitor exposure. Athymic nude mice bearing (V600E)BRAF-expressing human CRC cell line xenografts were treated with a small-molecule (V600E)BRAF inhibitor (or vehicle) daily for 10 d. Predictive (18)F-FLT PET was conducted before changes in tumor volume occurred. Correlations were evaluated among PET, inhibition of phosphorylated MEK (p-MEK) and phosphorylated-ERK (p-ERK) by Western blot, tumor proliferation by histology, and small-molecule exposure by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS).Treatment of CRC cell lines with PLX4720 reduced proliferation associated with target inhibition and upregulation of p27. In vivo, PLX4720 treatment reduced (18)F-FLT uptake, but not (18)F-FDG uptake, in Lim2405 xenografts before quantifiable differences in xenograft volume. Reduced (18)F-FLT PET reflected a modest, yet significant, reduction of Ki67 immunoreactivity, inhibition of p-MEK and p-ERK, and elevated tumor cell p27 protein levels. Both (18)F-FLT PET and (18)F-FDG PET accurately reflected a lack of response in HT-29 xenografts, which MALDI imaging mass spectrometry suggested may have stemmed from limited PLX4720 exposure.We used preclinical models of CRC to demonstrate (18)F-FLT PET as a sensitive predictor of response to (V600E)BRAF inhibitors. Because (18)F-FLT PET predicted reduced proliferation associated with attenuation of BRAF downstream effectors, yet (18)F-FDG PET did not, these data suggest that (18)F-FLT PET may represent an alternative to (18)F-FDG PET for quantifying clinical responses to BRAF inhibitors.

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Preclinical Applications of 3'-Deoxy-3'-[¹⁸F]Fluorothymidine in Oncology - A Systematic Review.

Publications

Preclinical Applications of 3'-Deoxy-3'-[<sup>18</sup>F]Fluorothymidine in Oncology - A Systematic Review.

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Dataset Information

Preclinical Applications of 3'-Deoxy-3'-[18F]Fluorothymidine in Oncology - A Systematic Review.

Publications

Preclinical Applications of 3'-Deoxy-3'-[&lt;sup&gt;18&lt;/sup&gt;F]Fluorothymidine in Oncology - A Systematic Review.

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OmicsDI is part of the ELIXIR infrastructure

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Preclinical Applications of 3'-Deoxy-3'-[¹⁸F]Fluorothymidine in Oncology - A Systematic Review.

Preclinical Applications of 3'-Deoxy-3'-[<sup>18</sup>F]Fluorothymidine in Oncology - A Systematic Review.