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Major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: Do preclinical studies with EGFR inhibitors suggest approaches to overcome some of the limitations

There are major hurdles to the use of tyrosine kinase inhibitors (TKIs) and any other agents with significant toxicities (which means practically the preponderance of potential effective agents) in the context of prevention/anti-progression (interception) studies. We will discuss epidermal growth fa...

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Autores principales: Dragnev, Konstantin H., Dragnev, Christo P. C., Lubet, Ronald A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165497/
https://www.ncbi.nlm.nih.gov/pubmed/37169023
http://dx.doi.org/10.3389/fcell.2023.1170444
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author Dragnev, Konstantin H.
Dragnev, Christo P. C.
Lubet, Ronald A.
author_facet Dragnev, Konstantin H.
Dragnev, Christo P. C.
Lubet, Ronald A.
author_sort Dragnev, Konstantin H.
collection PubMed
description There are major hurdles to the use of tyrosine kinase inhibitors (TKIs) and any other agents with significant toxicities (which means practically the preponderance of potential effective agents) in the context of prevention/anti-progression (interception) studies. We will discuss epidermal growth factor receptor (EGFR) inhibitors as examples, both in a primary prevention setting, where agent(s) are administered to individuals with no cancer but who might be considered at higher risk due to a variety of factors, and in anti-progression/interception studies, where agent(s) are administered to persons with known preinvasive lesions (e.g., colon adenomas, lung nodules, ductal carcinoma in situ (DCIS), or pancreatic intraepithelial neoplasia (PanIN) lesions in the pancreas) in an attempt to reverse or inhibit progression of these lesions. Multiple potential hurdles will be examined, including: a) toxicity of agents, b) the likely range of subtypes of cancers affected by a given treatment (e.g., EGFR inhibitors against EGFR mutant lung adenocarcinomas), c) the availability of practical endpoints besides the blocking of cancer formation or pharmacokinetics related to the agents administered in a primary prevention study, and d) the interpretation of the regression or blockage of new preinvasive lesions in the anti-progression study. Such an anti-progression approach may help address some of the factors commented on regarding primary prevention (toxicity, potential target organ cancer subtypes) but still leaves major questions regarding interpretation of modulation of preinvasive endpoints when it may not be clear how frequently they progress to clinical cancer. Additionally, we address whether certain recent preclinical findings might be able to reduce the toxicities associated with these agents and perhaps even increase their potential efficacy. Antibodies and TKIs other than the EGFR inhibitors are not discussed because few if any had been tested as monotherapies in humans, making their efficacy harder to predict, and because a number have relatively rare but quite striking toxicities. Furthermore, most of the practical hurdles raised regarding the EGFR inhibitors are relevant to the other TKIs. Finally, we briefly discuss whether early detection employing blood or serum samples may allow identification of high-risk groups more amenable to agents with greater toxicity.
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spelling pubmed-101654972023-05-09 Major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: Do preclinical studies with EGFR inhibitors suggest approaches to overcome some of the limitations Dragnev, Konstantin H. Dragnev, Christo P. C. Lubet, Ronald A. Front Cell Dev Biol Cell and Developmental Biology There are major hurdles to the use of tyrosine kinase inhibitors (TKIs) and any other agents with significant toxicities (which means practically the preponderance of potential effective agents) in the context of prevention/anti-progression (interception) studies. We will discuss epidermal growth factor receptor (EGFR) inhibitors as examples, both in a primary prevention setting, where agent(s) are administered to individuals with no cancer but who might be considered at higher risk due to a variety of factors, and in anti-progression/interception studies, where agent(s) are administered to persons with known preinvasive lesions (e.g., colon adenomas, lung nodules, ductal carcinoma in situ (DCIS), or pancreatic intraepithelial neoplasia (PanIN) lesions in the pancreas) in an attempt to reverse or inhibit progression of these lesions. Multiple potential hurdles will be examined, including: a) toxicity of agents, b) the likely range of subtypes of cancers affected by a given treatment (e.g., EGFR inhibitors against EGFR mutant lung adenocarcinomas), c) the availability of practical endpoints besides the blocking of cancer formation or pharmacokinetics related to the agents administered in a primary prevention study, and d) the interpretation of the regression or blockage of new preinvasive lesions in the anti-progression study. Such an anti-progression approach may help address some of the factors commented on regarding primary prevention (toxicity, potential target organ cancer subtypes) but still leaves major questions regarding interpretation of modulation of preinvasive endpoints when it may not be clear how frequently they progress to clinical cancer. Additionally, we address whether certain recent preclinical findings might be able to reduce the toxicities associated with these agents and perhaps even increase their potential efficacy. Antibodies and TKIs other than the EGFR inhibitors are not discussed because few if any had been tested as monotherapies in humans, making their efficacy harder to predict, and because a number have relatively rare but quite striking toxicities. Furthermore, most of the practical hurdles raised regarding the EGFR inhibitors are relevant to the other TKIs. Finally, we briefly discuss whether early detection employing blood or serum samples may allow identification of high-risk groups more amenable to agents with greater toxicity. Frontiers Media S.A. 2023-04-24 /pmc/articles/PMC10165497/ /pubmed/37169023 http://dx.doi.org/10.3389/fcell.2023.1170444 Text en Copyright © 2023 Dragnev, Dragnev and Lubet. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Dragnev, Konstantin H.
Dragnev, Christo P. C.
Lubet, Ronald A.
Major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: Do preclinical studies with EGFR inhibitors suggest approaches to overcome some of the limitations
title Major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: Do preclinical studies with EGFR inhibitors suggest approaches to overcome some of the limitations
title_full Major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: Do preclinical studies with EGFR inhibitors suggest approaches to overcome some of the limitations
title_fullStr Major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: Do preclinical studies with EGFR inhibitors suggest approaches to overcome some of the limitations
title_full_unstemmed Major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: Do preclinical studies with EGFR inhibitors suggest approaches to overcome some of the limitations
title_short Major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: Do preclinical studies with EGFR inhibitors suggest approaches to overcome some of the limitations
title_sort major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: do preclinical studies with egfr inhibitors suggest approaches to overcome some of the limitations
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165497/
https://www.ncbi.nlm.nih.gov/pubmed/37169023
http://dx.doi.org/10.3389/fcell.2023.1170444
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