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Depicting Changes in Tumor Biology in Response to Cetuximab Monotherapy or Combination Therapy by Apoptosis and Proliferation Imaging Using (18)F-ICMT-11 and (18)F-FLT PET
Imaging biomarkers must demonstrate their value in monitoring treatment. Two PET tracers, the caspase-3/7–specific isatin-5-sulfonamide (18)F-ICMT-11 ((18)F-(S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluoro-phenoxymethyl)-pyrrolidine-1-sulfonyl)isatin) and (18)F-FLT (3′-deo...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Society of Nuclear Medicine
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167530/ https://www.ncbi.nlm.nih.gov/pubmed/29794225 http://dx.doi.org/10.2967/jnumed.118.209304 |
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author | Heinzmann, Kathrin Nguyen, Quang-Dé Honess, Davina Smith, Donna-Michelle Stribbling, Stephen Brickute, Diana Barnes, Chris Griffiths, John Aboagye, Eric |
author_facet | Heinzmann, Kathrin Nguyen, Quang-Dé Honess, Davina Smith, Donna-Michelle Stribbling, Stephen Brickute, Diana Barnes, Chris Griffiths, John Aboagye, Eric |
author_sort | Heinzmann, Kathrin |
collection | PubMed |
description | Imaging biomarkers must demonstrate their value in monitoring treatment. Two PET tracers, the caspase-3/7–specific isatin-5-sulfonamide (18)F-ICMT-11 ((18)F-(S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluoro-phenoxymethyl)-pyrrolidine-1-sulfonyl)isatin) and (18)F-FLT (3′-deoxy-3′-(18)F-fluorothymidine), were used to detect early treatment-induced changes in tumor biology and determine whether any of these changes indicate a response to cetuximab, administered as monotherapy or combination therapy with gemcitabine. Methods: In mice bearing cetuximab-sensitive H1975 tumors (non–small lung cancer), the effects of single or repeated doses of the antiepidermal growth factor receptor antibody cetuximab (10 mg/kg on day 1 only or on days 1 and 2) or a single dose of gemcitabine (125 mg/kg on day 2) were investigated by (18)F-ICMT-11 or (18)F-FLT on day 3. Imaging was also performed after 2 doses of cetuximab (days 1 and 2) in mice bearing cetuximab-insensitive HCT116 tumors (colorectal cancer). For imaging–histology comparison, tumors were evaluated for proliferation (Ki-67 and thymidine kinase 1 [TK1]), cell death (cleaved caspase-3 and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling [TUNEL]), and target engagement (epidermal growth factor receptor expression) by immunohistochemistry, immunofluorescence, and immunoblotting, respectively. Tumor and plasma were analyzed for thymidine and gemcitabine metabolites by liquid chromatography–mass spectrometry. Results: Retention of both tracers was sensitive to cetuximab in H1975 tumors. (18)F-ICMT-11 uptake and ex vivo cleaved caspase-3 staining notably increased in tumors treated with repeated doses of cetuximab (75%) and combination treatment (46%). Although a single dose of cetuximab was insufficient to induce apoptosis, it did affect proliferation. Significant reductions in tumor (18)F-FLT uptake (44%–50%; P < 0.001) induced by cetuximab monotherapy and combination therapy were paralleled by a clear decrease in proliferation (Ki-67 decrease, 72%–95%; P < 0.0001), followed by a marked tumor growth delay. TK1 expression and tumor thymidine concentrations were profoundly reduced. Neither imaging tracer depicted the gemcitabine-induced tumor changes. However, cleaved caspase-3 and Ki-67 staining did not significantly differ after gemcitabine treatment whereas TK1 expression and thymidine concentrations increased. No cetuximab-induced modulation of the imaging tracers or other response markers was detected in the insensitive model of HCT116. Conclusion: (18)F-ICMT-11 and (18)F-FLT are valuable tools to assess cetuximab sensitivity depicting distinct and time-variant aspects of treatment response. |
format | Online Article Text |
id | pubmed-6167530 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Society of Nuclear Medicine |
record_format | MEDLINE/PubMed |
spelling | pubmed-61675302018-10-03 Depicting Changes in Tumor Biology in Response to Cetuximab Monotherapy or Combination Therapy by Apoptosis and Proliferation Imaging Using (18)F-ICMT-11 and (18)F-FLT PET Heinzmann, Kathrin Nguyen, Quang-Dé Honess, Davina Smith, Donna-Michelle Stribbling, Stephen Brickute, Diana Barnes, Chris Griffiths, John Aboagye, Eric J Nucl Med Oncology Imaging biomarkers must demonstrate their value in monitoring treatment. Two PET tracers, the caspase-3/7–specific isatin-5-sulfonamide (18)F-ICMT-11 ((18)F-(S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluoro-phenoxymethyl)-pyrrolidine-1-sulfonyl)isatin) and (18)F-FLT (3′-deoxy-3′-(18)F-fluorothymidine), were used to detect early treatment-induced changes in tumor biology and determine whether any of these changes indicate a response to cetuximab, administered as monotherapy or combination therapy with gemcitabine. Methods: In mice bearing cetuximab-sensitive H1975 tumors (non–small lung cancer), the effects of single or repeated doses of the antiepidermal growth factor receptor antibody cetuximab (10 mg/kg on day 1 only or on days 1 and 2) or a single dose of gemcitabine (125 mg/kg on day 2) were investigated by (18)F-ICMT-11 or (18)F-FLT on day 3. Imaging was also performed after 2 doses of cetuximab (days 1 and 2) in mice bearing cetuximab-insensitive HCT116 tumors (colorectal cancer). For imaging–histology comparison, tumors were evaluated for proliferation (Ki-67 and thymidine kinase 1 [TK1]), cell death (cleaved caspase-3 and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling [TUNEL]), and target engagement (epidermal growth factor receptor expression) by immunohistochemistry, immunofluorescence, and immunoblotting, respectively. Tumor and plasma were analyzed for thymidine and gemcitabine metabolites by liquid chromatography–mass spectrometry. Results: Retention of both tracers was sensitive to cetuximab in H1975 tumors. (18)F-ICMT-11 uptake and ex vivo cleaved caspase-3 staining notably increased in tumors treated with repeated doses of cetuximab (75%) and combination treatment (46%). Although a single dose of cetuximab was insufficient to induce apoptosis, it did affect proliferation. Significant reductions in tumor (18)F-FLT uptake (44%–50%; P < 0.001) induced by cetuximab monotherapy and combination therapy were paralleled by a clear decrease in proliferation (Ki-67 decrease, 72%–95%; P < 0.0001), followed by a marked tumor growth delay. TK1 expression and tumor thymidine concentrations were profoundly reduced. Neither imaging tracer depicted the gemcitabine-induced tumor changes. However, cleaved caspase-3 and Ki-67 staining did not significantly differ after gemcitabine treatment whereas TK1 expression and thymidine concentrations increased. No cetuximab-induced modulation of the imaging tracers or other response markers was detected in the insensitive model of HCT116. Conclusion: (18)F-ICMT-11 and (18)F-FLT are valuable tools to assess cetuximab sensitivity depicting distinct and time-variant aspects of treatment response. Society of Nuclear Medicine 2018-10 /pmc/articles/PMC6167530/ /pubmed/29794225 http://dx.doi.org/10.2967/jnumed.118.209304 Text en © 2018 by the Society of Nuclear Medicine and Molecular Imaging. Immediate Open Access: Creative Commons Attribution 4.0 International License (CC BY) allows users to share and adapt with attribution, excluding materials credited to previous publications. License: https://creativecommons.org/licenses/by/4.0/. Details: http://jnm.snmjournals.org/site/misc/permission.xhtml. |
spellingShingle | Oncology Heinzmann, Kathrin Nguyen, Quang-Dé Honess, Davina Smith, Donna-Michelle Stribbling, Stephen Brickute, Diana Barnes, Chris Griffiths, John Aboagye, Eric Depicting Changes in Tumor Biology in Response to Cetuximab Monotherapy or Combination Therapy by Apoptosis and Proliferation Imaging Using (18)F-ICMT-11 and (18)F-FLT PET |
title | Depicting Changes in Tumor Biology in Response to Cetuximab Monotherapy or Combination Therapy by Apoptosis and Proliferation Imaging Using (18)F-ICMT-11 and (18)F-FLT PET |
title_full | Depicting Changes in Tumor Biology in Response to Cetuximab Monotherapy or Combination Therapy by Apoptosis and Proliferation Imaging Using (18)F-ICMT-11 and (18)F-FLT PET |
title_fullStr | Depicting Changes in Tumor Biology in Response to Cetuximab Monotherapy or Combination Therapy by Apoptosis and Proliferation Imaging Using (18)F-ICMT-11 and (18)F-FLT PET |
title_full_unstemmed | Depicting Changes in Tumor Biology in Response to Cetuximab Monotherapy or Combination Therapy by Apoptosis and Proliferation Imaging Using (18)F-ICMT-11 and (18)F-FLT PET |
title_short | Depicting Changes in Tumor Biology in Response to Cetuximab Monotherapy or Combination Therapy by Apoptosis and Proliferation Imaging Using (18)F-ICMT-11 and (18)F-FLT PET |
title_sort | depicting changes in tumor biology in response to cetuximab monotherapy or combination therapy by apoptosis and proliferation imaging using (18)f-icmt-11 and (18)f-flt pet |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167530/ https://www.ncbi.nlm.nih.gov/pubmed/29794225 http://dx.doi.org/10.2967/jnumed.118.209304 |
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