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Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies

Pancreatic cancer is the fourth leading cause of cancer death in the US and is expected to become the second leading cause of cancer-related deaths in the next decade. Despite 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel significantly improvin...

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Autores principales: Chiorean, Elena Gabriela, Coveler, Andrew L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500614/
https://www.ncbi.nlm.nih.gov/pubmed/26185420
http://dx.doi.org/10.2147/DDDT.S60328
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author Chiorean, Elena Gabriela
Coveler, Andrew L
author_facet Chiorean, Elena Gabriela
Coveler, Andrew L
author_sort Chiorean, Elena Gabriela
collection PubMed
description Pancreatic cancer is the fourth leading cause of cancer death in the US and is expected to become the second leading cause of cancer-related deaths in the next decade. Despite 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel significantly improving outcomes for metastatic cancer, refractory disease still poses significant challenges. Difficulties with early detection and the inherent chemo- and radio-resistant nature of this malignancy led to attempts to define the sequential biology of pancreatic cancer in order to improve survival outcomes. Pancreatic adenocarcinoma is characterized by several germline or acquired genetic mutations, the most common being KRAS (90%), CDK2NA (90%), TP53 (75%–90%), DPC4/SMAD4 (50%). In addition, the tumor microenvironment, chemoresistant cancer stem cells, and the desmoplastic stroma have been the target of some promising clinical investigations. Among the core pathways reproducibly shown to lead the development and progression of this disease, DNA repair, apoptosis, G1/S cell cycle transition, KRAS, Wnt, Notch, Hedgehog, TGF-beta, and other cell invasion pathways, have been the target of “precision therapeutics”. No single molecularly targeted therapeutic though has been uniformly successful, probably due to the tumor heterogeneity, but biomarker research is evolving and it hopes to select more patients likely to benefit. Recent reports note activity with immunotherapies such as CD40 agonists, CCR2 inhibitors, cancer vaccines, and novel combinations against the immunosuppressive tumor milieu are ongoing. While many obstacles still exist, clearly we are making progress in deciphering the heterogeneity within pancreatic cancers. Integrating conventional and immunological targeting will be the key to effective treatment of this deadly disease.
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spelling pubmed-45006142015-07-16 Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies Chiorean, Elena Gabriela Coveler, Andrew L Drug Des Devel Ther Review Pancreatic cancer is the fourth leading cause of cancer death in the US and is expected to become the second leading cause of cancer-related deaths in the next decade. Despite 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel significantly improving outcomes for metastatic cancer, refractory disease still poses significant challenges. Difficulties with early detection and the inherent chemo- and radio-resistant nature of this malignancy led to attempts to define the sequential biology of pancreatic cancer in order to improve survival outcomes. Pancreatic adenocarcinoma is characterized by several germline or acquired genetic mutations, the most common being KRAS (90%), CDK2NA (90%), TP53 (75%–90%), DPC4/SMAD4 (50%). In addition, the tumor microenvironment, chemoresistant cancer stem cells, and the desmoplastic stroma have been the target of some promising clinical investigations. Among the core pathways reproducibly shown to lead the development and progression of this disease, DNA repair, apoptosis, G1/S cell cycle transition, KRAS, Wnt, Notch, Hedgehog, TGF-beta, and other cell invasion pathways, have been the target of “precision therapeutics”. No single molecularly targeted therapeutic though has been uniformly successful, probably due to the tumor heterogeneity, but biomarker research is evolving and it hopes to select more patients likely to benefit. Recent reports note activity with immunotherapies such as CD40 agonists, CCR2 inhibitors, cancer vaccines, and novel combinations against the immunosuppressive tumor milieu are ongoing. While many obstacles still exist, clearly we are making progress in deciphering the heterogeneity within pancreatic cancers. Integrating conventional and immunological targeting will be the key to effective treatment of this deadly disease. Dove Medical Press 2015-07-07 /pmc/articles/PMC4500614/ /pubmed/26185420 http://dx.doi.org/10.2147/DDDT.S60328 Text en © 2015 Chiorean and Coveler. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Review
Chiorean, Elena Gabriela
Coveler, Andrew L
Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies
title Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies
title_full Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies
title_fullStr Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies
title_full_unstemmed Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies
title_short Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies
title_sort pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500614/
https://www.ncbi.nlm.nih.gov/pubmed/26185420
http://dx.doi.org/10.2147/DDDT.S60328
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