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Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and suppor...

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Autores principales: Candido, Marina Ferreira, Medeiros, Mariana, Veronez, Luciana Chain, Bastos, David, Oliveira, Karla Laissa, Pezuk, Julia Alejandra, Valera, Elvis Terci, Brassesco, María Sol
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9966033/
https://www.ncbi.nlm.nih.gov/pubmed/36839989
http://dx.doi.org/10.3390/pharmaceutics15020664
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author Candido, Marina Ferreira
Medeiros, Mariana
Veronez, Luciana Chain
Bastos, David
Oliveira, Karla Laissa
Pezuk, Julia Alejandra
Valera, Elvis Terci
Brassesco, María Sol
author_facet Candido, Marina Ferreira
Medeiros, Mariana
Veronez, Luciana Chain
Bastos, David
Oliveira, Karla Laissa
Pezuk, Julia Alejandra
Valera, Elvis Terci
Brassesco, María Sol
author_sort Candido, Marina Ferreira
collection PubMed
description Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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spelling pubmed-99660332023-02-26 Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario Candido, Marina Ferreira Medeiros, Mariana Veronez, Luciana Chain Bastos, David Oliveira, Karla Laissa Pezuk, Julia Alejandra Valera, Elvis Terci Brassesco, María Sol Pharmaceutics Review Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism. MDPI 2023-02-16 /pmc/articles/PMC9966033/ /pubmed/36839989 http://dx.doi.org/10.3390/pharmaceutics15020664 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Candido, Marina Ferreira
Medeiros, Mariana
Veronez, Luciana Chain
Bastos, David
Oliveira, Karla Laissa
Pezuk, Julia Alejandra
Valera, Elvis Terci
Brassesco, María Sol
Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario
title Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario
title_full Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario
title_fullStr Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario
title_full_unstemmed Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario
title_short Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario
title_sort drugging hijacked kinase pathways in pediatric oncology: opportunities and current scenario
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9966033/
https://www.ncbi.nlm.nih.gov/pubmed/36839989
http://dx.doi.org/10.3390/pharmaceutics15020664
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