Correlation of hypoxia PET tracer uptake with hypoxic radioresistance in cancer cells: PET biomarkers of resistance to stereotactic radiation therapy?

Kazumi Chia; Rowena L. Paul; Amanda J. Weeks; Marium Naeem; Gregory E.D. Mullen; David Landau; Philip J. Blower

doi:10.1016/j.nucmedbio.2022.04.004

Correlation of hypoxia PET tracer uptake with hypoxic radioresistance in cancer cells: PET biomarkers of resistance to stereotactic radiation therapy?

Kazumi Chia^*, Rowena L. Paul, Amanda J. Weeks, Marium Naeem, Gregory E.D. Mullen, David Landau, Philip J. Blower

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: The pO₂ threshold of an ideal PET hypoxia tracer for radiotherapy planning in cancer would match those observed in clinically and biologically relevant processes such as radioresistance and HIF1α expression. To identify such tracers, we directly compared uptake in vitro of hypoxia PET tracers ([¹⁸F]FMISO, [⁶⁴Cu]CuATSM, and analogues [⁶⁴Cu]CuATS, [⁶⁴Cu]CuATSE, [⁶⁴Cu]CuCTS, [⁶⁴Cu]CuDTS, [⁶⁴Cu]CuDTSE, [⁶⁴Cu]CuDTSM) with levels of radioresistance and HIF1α expression in cultured cancer cells under identical hypoxic conditions ranging from extreme hypoxia to normoxia. Pimonidazole uptake was also compared as a marker of hypoxia. Methods: A custom-built hypoxia apparatus enabled all experiments to be performed under identical hypoxic conditions with constant measurement of pO₂ in media using an OxyLab pO₂™ probe. HCT116 human colonic carcinoma and MCF-7 human Caucasian breast adenocarcinoma cells were irradiated using a cobalt teletherapy unit. Clonogenic assays were used to assess survival. HIF1α expression was determined by western blotting, tracer uptake by gamma counting and pimonidazole binding by flow cytometry. Results: Radioresistance, pimonidazole binding and HIF1α expression increased gradually as pO₂ decreased between 25 mmHg and 0 mmHg. In contrast, all the PET hypoxia tracers showed a sharp increase in uptake only when pO₂ levels fell below 1 mmHg. Above this threshold, tracer uptake was not elevated above that in normoxic cells. Conclusion: This study highlights an important mismatch in pO₂ thresholds between these PET tracers and other markers of hypoxia: tracer uptake only occurred at oxygen levels that were well below levels that induced radioresistance, pimonidazole uptake and HIF1α expression. Although their pO₂ thresholds do not match the threshold for resistance to conventionally fractionated radiotherapy (pO₂ 2.5–10 mmHg), their specificity for extreme hypoxia (pO₂ ≪ 1 mmHg) suggests these PET tracers may be of particular use to predict outcomes in stereotactic radiation therapy where these maximally resistant cells play a key role in determining the biological effect.

Original language	English
Pages (from-to)	10-17
Number of pages	8
Journal	Nuclear Medicine and Biology
Volume	110-111
DOIs	https://doi.org/10.1016/j.nucmedbio.2022.04.004
Publication status	Published - 1 Jul 2022

Keywords

HIF1α
Hypoxia
PET
Radioresistance
Stereotactic radiation therapy
Tracer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.nucmedbio.2022.04.004

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@article{e23b4b26706d43b19b7578f395e6e7e3,

title = "Correlation of hypoxia PET tracer uptake with hypoxic radioresistance in cancer cells: PET biomarkers of resistance to stereotactic radiation therapy?",

abstract = "Purpose: The pO2 threshold of an ideal PET hypoxia tracer for radiotherapy planning in cancer would match those observed in clinically and biologically relevant processes such as radioresistance and HIF1α expression. To identify such tracers, we directly compared uptake in vitro of hypoxia PET tracers ([18F]FMISO, [64Cu]CuATSM, and analogues [64Cu]CuATS, [64Cu]CuATSE, [64Cu]CuCTS, [64Cu]CuDTS, [64Cu]CuDTSE, [64Cu]CuDTSM) with levels of radioresistance and HIF1α expression in cultured cancer cells under identical hypoxic conditions ranging from extreme hypoxia to normoxia. Pimonidazole uptake was also compared as a marker of hypoxia. Methods: A custom-built hypoxia apparatus enabled all experiments to be performed under identical hypoxic conditions with constant measurement of pO2 in media using an OxyLab pO2{\texttrademark} probe. HCT116 human colonic carcinoma and MCF-7 human Caucasian breast adenocarcinoma cells were irradiated using a cobalt teletherapy unit. Clonogenic assays were used to assess survival. HIF1α expression was determined by western blotting, tracer uptake by gamma counting and pimonidazole binding by flow cytometry. Results: Radioresistance, pimonidazole binding and HIF1α expression increased gradually as pO2 decreased between 25 mmHg and 0 mmHg. In contrast, all the PET hypoxia tracers showed a sharp increase in uptake only when pO2 levels fell below 1 mmHg. Above this threshold, tracer uptake was not elevated above that in normoxic cells. Conclusion: This study highlights an important mismatch in pO2 thresholds between these PET tracers and other markers of hypoxia: tracer uptake only occurred at oxygen levels that were well below levels that induced radioresistance, pimonidazole uptake and HIF1α expression. Although their pO2 thresholds do not match the threshold for resistance to conventionally fractionated radiotherapy (pO2 2.5–10 mmHg), their specificity for extreme hypoxia (pO2 ≪ 1 mmHg) suggests these PET tracers may be of particular use to predict outcomes in stereotactic radiation therapy where these maximally resistant cells play a key role in determining the biological effect.",

keywords = "HIF1α, Hypoxia, PET, Radioresistance, Stereotactic radiation therapy, Tracer",

author = "Kazumi Chia and Paul, {Rowena L.} and Weeks, {Amanda J.} and Marium Naeem and Mullen, {Gregory E.D.} and David Landau and Blower, {Philip J.}",

note = "Funding Information: This work was supported by the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and EPSRC ( WT088641/Z/09/Z , WT 203148/Z/16/Z ), the KCL-UCL Comprehensive Cancer Imaging Centre funded by Cancer Research UK & EPSRC , in association with the MRC and the Department of Health (England), EPSRC Programme Grant [ EP/S032789/1 , “MITHRAS”], a Wellcome Trust Multi-User Equipment Grant ( WT212885/Z/18/Z ) and the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. K.C. received a Cancer Research UK Clinical Training Fellowship and A.J.W. was supported by a grant from the Guy's and St. Thomas' Charity (Grant to P.J.B.). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the DoH. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = jul,

day = "1",

doi = "10.1016/j.nucmedbio.2022.04.004",

language = "English",

volume = "110-111",

pages = "10--17",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Correlation of hypoxia PET tracer uptake with hypoxic radioresistance in cancer cells

T2 - PET biomarkers of resistance to stereotactic radiation therapy?

AU - Chia, Kazumi

AU - Paul, Rowena L.

AU - Weeks, Amanda J.

AU - Naeem, Marium

AU - Mullen, Gregory E.D.

AU - Landau, David

AU - Blower, Philip J.

N1 - Funding Information: This work was supported by the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and EPSRC ( WT088641/Z/09/Z , WT 203148/Z/16/Z ), the KCL-UCL Comprehensive Cancer Imaging Centre funded by Cancer Research UK & EPSRC , in association with the MRC and the Department of Health (England), EPSRC Programme Grant [ EP/S032789/1 , “MITHRAS”], a Wellcome Trust Multi-User Equipment Grant ( WT212885/Z/18/Z ) and the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. K.C. received a Cancer Research UK Clinical Training Fellowship and A.J.W. was supported by a grant from the Guy's and St. Thomas' Charity (Grant to P.J.B.). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the DoH. Publisher Copyright: © 2022 The Authors

PY - 2022/7/1

Y1 - 2022/7/1

N2 - Purpose: The pO2 threshold of an ideal PET hypoxia tracer for radiotherapy planning in cancer would match those observed in clinically and biologically relevant processes such as radioresistance and HIF1α expression. To identify such tracers, we directly compared uptake in vitro of hypoxia PET tracers ([18F]FMISO, [64Cu]CuATSM, and analogues [64Cu]CuATS, [64Cu]CuATSE, [64Cu]CuCTS, [64Cu]CuDTS, [64Cu]CuDTSE, [64Cu]CuDTSM) with levels of radioresistance and HIF1α expression in cultured cancer cells under identical hypoxic conditions ranging from extreme hypoxia to normoxia. Pimonidazole uptake was also compared as a marker of hypoxia. Methods: A custom-built hypoxia apparatus enabled all experiments to be performed under identical hypoxic conditions with constant measurement of pO2 in media using an OxyLab pO2™ probe. HCT116 human colonic carcinoma and MCF-7 human Caucasian breast adenocarcinoma cells were irradiated using a cobalt teletherapy unit. Clonogenic assays were used to assess survival. HIF1α expression was determined by western blotting, tracer uptake by gamma counting and pimonidazole binding by flow cytometry. Results: Radioresistance, pimonidazole binding and HIF1α expression increased gradually as pO2 decreased between 25 mmHg and 0 mmHg. In contrast, all the PET hypoxia tracers showed a sharp increase in uptake only when pO2 levels fell below 1 mmHg. Above this threshold, tracer uptake was not elevated above that in normoxic cells. Conclusion: This study highlights an important mismatch in pO2 thresholds between these PET tracers and other markers of hypoxia: tracer uptake only occurred at oxygen levels that were well below levels that induced radioresistance, pimonidazole uptake and HIF1α expression. Although their pO2 thresholds do not match the threshold for resistance to conventionally fractionated radiotherapy (pO2 2.5–10 mmHg), their specificity for extreme hypoxia (pO2 ≪ 1 mmHg) suggests these PET tracers may be of particular use to predict outcomes in stereotactic radiation therapy where these maximally resistant cells play a key role in determining the biological effect.

AB - Purpose: The pO2 threshold of an ideal PET hypoxia tracer for radiotherapy planning in cancer would match those observed in clinically and biologically relevant processes such as radioresistance and HIF1α expression. To identify such tracers, we directly compared uptake in vitro of hypoxia PET tracers ([18F]FMISO, [64Cu]CuATSM, and analogues [64Cu]CuATS, [64Cu]CuATSE, [64Cu]CuCTS, [64Cu]CuDTS, [64Cu]CuDTSE, [64Cu]CuDTSM) with levels of radioresistance and HIF1α expression in cultured cancer cells under identical hypoxic conditions ranging from extreme hypoxia to normoxia. Pimonidazole uptake was also compared as a marker of hypoxia. Methods: A custom-built hypoxia apparatus enabled all experiments to be performed under identical hypoxic conditions with constant measurement of pO2 in media using an OxyLab pO2™ probe. HCT116 human colonic carcinoma and MCF-7 human Caucasian breast adenocarcinoma cells were irradiated using a cobalt teletherapy unit. Clonogenic assays were used to assess survival. HIF1α expression was determined by western blotting, tracer uptake by gamma counting and pimonidazole binding by flow cytometry. Results: Radioresistance, pimonidazole binding and HIF1α expression increased gradually as pO2 decreased between 25 mmHg and 0 mmHg. In contrast, all the PET hypoxia tracers showed a sharp increase in uptake only when pO2 levels fell below 1 mmHg. Above this threshold, tracer uptake was not elevated above that in normoxic cells. Conclusion: This study highlights an important mismatch in pO2 thresholds between these PET tracers and other markers of hypoxia: tracer uptake only occurred at oxygen levels that were well below levels that induced radioresistance, pimonidazole uptake and HIF1α expression. Although their pO2 thresholds do not match the threshold for resistance to conventionally fractionated radiotherapy (pO2 2.5–10 mmHg), their specificity for extreme hypoxia (pO2 ≪ 1 mmHg) suggests these PET tracers may be of particular use to predict outcomes in stereotactic radiation therapy where these maximally resistant cells play a key role in determining the biological effect.

KW - HIF1α

KW - Hypoxia

KW - PET

KW - Radioresistance

KW - Stereotactic radiation therapy

KW - Tracer

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U2 - 10.1016/j.nucmedbio.2022.04.004

DO - 10.1016/j.nucmedbio.2022.04.004

M3 - Article

C2 - 35468342

AN - SCOPUS:85129266208

SN - 0969-8051

VL - 110-111

SP - 10

EP - 17

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

ER -

Correlation of hypoxia PET tracer uptake with hypoxic radioresistance in cancer cells: PET biomarkers of resistance to stereotactic radiation therapy?

Abstract

Keywords

UN SDGs

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