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In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours

BACKGROUND: Targeted therapies elicit anticancer activity by exerting pharmacodynamic effects on specific molecular targets. Currently, there is limited use of pharmacodynamic assessment to guide drug administration in the routine oncology setting. METHODS: We developed a phosphoshift (pShift) flow...

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Autores principales: Quintela-Fandino, M, Krzyzanowska, M, Duncan, G, Young, A, Moore, M J, Chen, E X, Stathis, A, Colomer, R, Petronis, J, Grewal, M, Webster, S, Wang, L, Siu, L L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619253/
https://www.ncbi.nlm.nih.gov/pubmed/23412107
http://dx.doi.org/10.1038/bjc.2013.64
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author Quintela-Fandino, M
Krzyzanowska, M
Duncan, G
Young, A
Moore, M J
Chen, E X
Stathis, A
Colomer, R
Petronis, J
Grewal, M
Webster, S
Wang, L
Siu, L L
author_facet Quintela-Fandino, M
Krzyzanowska, M
Duncan, G
Young, A
Moore, M J
Chen, E X
Stathis, A
Colomer, R
Petronis, J
Grewal, M
Webster, S
Wang, L
Siu, L L
author_sort Quintela-Fandino, M
collection PubMed
description BACKGROUND: Targeted therapies elicit anticancer activity by exerting pharmacodynamic effects on specific molecular targets. Currently, there is limited use of pharmacodynamic assessment to guide drug administration in the routine oncology setting. METHODS: We developed a phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells, and evaluated it in a phase II clinical trial of oral sorafenib plus low-dose cyclophosphamide in patients with advanced neuroendocrine tumours (NETs), in order to predict clinical course and/or guide individual dose-titration. RESULTS: Twenty-two patients were enrolled. Median progression-free survival (PFS) was 3 months (95% CI 2–10.7), and one patient had a partial response. PFS was longer among five patients who demonstrated an increase in pShift after 7 days of sorafenib compared with those who did not (14.9 months vs 2.8 months; P=0.047). However, pShift did not add value to toxicity-based dose-titration. CONCLUSION: The pharmacodynamic assessment of RAF transduction may identify selected patients with advanced NETs most likely to benefit from the combination of sorafenib plus cyclophosphamide. Further investigation of this test as a potential biomarker is warranted.
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spelling pubmed-36192532014-04-02 In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours Quintela-Fandino, M Krzyzanowska, M Duncan, G Young, A Moore, M J Chen, E X Stathis, A Colomer, R Petronis, J Grewal, M Webster, S Wang, L Siu, L L Br J Cancer Translational Therapeutics BACKGROUND: Targeted therapies elicit anticancer activity by exerting pharmacodynamic effects on specific molecular targets. Currently, there is limited use of pharmacodynamic assessment to guide drug administration in the routine oncology setting. METHODS: We developed a phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells, and evaluated it in a phase II clinical trial of oral sorafenib plus low-dose cyclophosphamide in patients with advanced neuroendocrine tumours (NETs), in order to predict clinical course and/or guide individual dose-titration. RESULTS: Twenty-two patients were enrolled. Median progression-free survival (PFS) was 3 months (95% CI 2–10.7), and one patient had a partial response. PFS was longer among five patients who demonstrated an increase in pShift after 7 days of sorafenib compared with those who did not (14.9 months vs 2.8 months; P=0.047). However, pShift did not add value to toxicity-based dose-titration. CONCLUSION: The pharmacodynamic assessment of RAF transduction may identify selected patients with advanced NETs most likely to benefit from the combination of sorafenib plus cyclophosphamide. Further investigation of this test as a potential biomarker is warranted. Nature Publishing Group 2013-04-02 2013-02-14 /pmc/articles/PMC3619253/ /pubmed/23412107 http://dx.doi.org/10.1038/bjc.2013.64 Text en Copyright © 2013 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Translational Therapeutics
Quintela-Fandino, M
Krzyzanowska, M
Duncan, G
Young, A
Moore, M J
Chen, E X
Stathis, A
Colomer, R
Petronis, J
Grewal, M
Webster, S
Wang, L
Siu, L L
In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours
title In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours
title_full In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours
title_fullStr In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours
title_full_unstemmed In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours
title_short In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours
title_sort in vivo raf signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619253/
https://www.ncbi.nlm.nih.gov/pubmed/23412107
http://dx.doi.org/10.1038/bjc.2013.64
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