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Targeting gastric cancer with trastuzumab: new clinical practice and innovative developments to overcome resistance.

Roukos DH - Ann. Surg. Oncol. (2009)

View Article: PubMed Central - PubMed

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A new molecular classification and novel targeted therapy can improve poor oncological outcomes of some patients with gastric cancer... Each year 900,000 patients are diagnosed worldwide with gastric cancer... Potentially, approximately 25% of these patients may benefit by adding trastuzumab to current standard treatment... Inhibition of signaling cascades may suppress cancer cell proliferation and survival... However, for most solid tumors, clinical efficacy measured by overall survival benefit is modest... Phase III trials confirming preclinical and clinical data for the safety and efficacy of trastuzumab independently of robust clinicopathologic factors in both metastatic and adjuvant setting have led to the establishment of this antibody as standard treatment for HER2-positive breast cancer. – However, there has been no such evidence for any other cancer... Based on a pivotal phase III study, lapatinib in combination with capecitabine has been approved by the FDA for use in patients with advanced HER2-positive breast cancer who have previously received trastuzumab... Therefore, lapatinib alone or in combination with trastuzumab, which was shown to be superior to a single agent, are potential effective therapies to overcome trastuzumab resistance in HER2-positive gastric cancer... Given the current strong evidence that multiple genetic alterations and several signaling pathways are dysregulated in solid cancers, one of the most rational approaches is to inhibit these pathways... Combining targeted agents and considering crosstalk between pathways and bypass of targeted agents as well as predictors of response might lead to highly effective therapies... Rapid advances in molecular systems biology and future cheaper whole-genome cancer data scans are innovative exciting developments towards the development of novel response predictors and a new generation of multitargeted agents., The new era of personalized cancer care is here, but multiple challenges including major funding requirements and reliable data analysis make the translation of personalized research approaches into clinical medical practice difficult... Addition of trastuzumab to chemotherapy improves overall survival and is a new standard treatment for patients with locally advanced, recurrent or metastatic HER2-positive disease... Lapatinib and other novel antibodies or TKIs tested in clinical trials for HER2-positive breast cancer might also prove effective in trastuzumab-resistant HER2-positive gastric cancer... Understanding genotypic–phenotypic cancer diversity and signaling feedback loops as well as developing reliable methods to screen for identifying dysregulated signaling pathways in individual patients is a rational and exciting approach... If successful, such comprehensive approaches using molecular systems biology and future whole-genome cancer data scans may result in the discovery of novel multitargeted therapies tailored to individual patients on the basis of novel predictors of response to combined therapies.

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a Ligand binding and subsequent Erbb dimer formation initiates signaling through a complex array of intracellular pathways that initiate and control a range of cellular processes. Dimer formation results in the cross-phosphorylation of the dimer partners, creating docking sites that allow the recruitment of downstream signaling components and the formation of signaling complexes. Two key signaling pathways activated by the Erbb family dimers are the MAPK pathway, which stimulates proliferation, and the PI3K–Akt pathway, which promotes tumor cell survival (see the figure). Only signaling through these two pathways and some of the known outcomes are shown here for simplicity. b The antibody trastuzumab binds directly to domain IV of the extracellular region of ERBB2, suppressing ERBB2 signaling activity, preventing cleavage of the extracellular domain, and marking tumor cells that overexpress ERBB2 for further immunological attack through antibody-dependent cell-mediated cytotoxicity. GSK3β, glycogen synthase kinase 3β; NF-κB, nuclear factor-κB; PDK1, pyruvate dehydrogenase kinase 1; PIP2, phosphatidylinositol biphosphate; PIP3, phosphatidylinositol triphosphate
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Fig1: a Ligand binding and subsequent Erbb dimer formation initiates signaling through a complex array of intracellular pathways that initiate and control a range of cellular processes. Dimer formation results in the cross-phosphorylation of the dimer partners, creating docking sites that allow the recruitment of downstream signaling components and the formation of signaling complexes. Two key signaling pathways activated by the Erbb family dimers are the MAPK pathway, which stimulates proliferation, and the PI3K–Akt pathway, which promotes tumor cell survival (see the figure). Only signaling through these two pathways and some of the known outcomes are shown here for simplicity. b The antibody trastuzumab binds directly to domain IV of the extracellular region of ERBB2, suppressing ERBB2 signaling activity, preventing cleavage of the extracellular domain, and marking tumor cells that overexpress ERBB2 for further immunological attack through antibody-dependent cell-mediated cytotoxicity. GSK3β, glycogen synthase kinase 3β; NF-κB, nuclear factor-κB; PDK1, pyruvate dehydrogenase kinase 1; PIP2, phosphatidylinositol biphosphate; PIP3, phosphatidylinositol triphosphate

Mentions: The Erbb family consists of four closely related type 1 transmembrane tyrosine kinase receptors: EGFR (or HER1), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). Each receptor comprises an extracellular domain at which ligand binding occurs, an α-helical transmembrane segment, and an intracellular protein tyrosine kinase domain. Ligand binding to these EGF family receptors phosphorylates and activates a complex intracellular signaling pathways network that controls a range of cellular processes including proliferation, angiogenesis, cell cycle, survival, and apoptosis (Fig. 1a).3Fig. 1


Targeting gastric cancer with trastuzumab: new clinical practice and innovative developments to overcome resistance.

Roukos DH - Ann. Surg. Oncol. (2009)

a Ligand binding and subsequent Erbb dimer formation initiates signaling through a complex array of intracellular pathways that initiate and control a range of cellular processes. Dimer formation results in the cross-phosphorylation of the dimer partners, creating docking sites that allow the recruitment of downstream signaling components and the formation of signaling complexes. Two key signaling pathways activated by the Erbb family dimers are the MAPK pathway, which stimulates proliferation, and the PI3K–Akt pathway, which promotes tumor cell survival (see the figure). Only signaling through these two pathways and some of the known outcomes are shown here for simplicity. b The antibody trastuzumab binds directly to domain IV of the extracellular region of ERBB2, suppressing ERBB2 signaling activity, preventing cleavage of the extracellular domain, and marking tumor cells that overexpress ERBB2 for further immunological attack through antibody-dependent cell-mediated cytotoxicity. GSK3β, glycogen synthase kinase 3β; NF-κB, nuclear factor-κB; PDK1, pyruvate dehydrogenase kinase 1; PIP2, phosphatidylinositol biphosphate; PIP3, phosphatidylinositol triphosphate
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2805793&req=5

Fig1: a Ligand binding and subsequent Erbb dimer formation initiates signaling through a complex array of intracellular pathways that initiate and control a range of cellular processes. Dimer formation results in the cross-phosphorylation of the dimer partners, creating docking sites that allow the recruitment of downstream signaling components and the formation of signaling complexes. Two key signaling pathways activated by the Erbb family dimers are the MAPK pathway, which stimulates proliferation, and the PI3K–Akt pathway, which promotes tumor cell survival (see the figure). Only signaling through these two pathways and some of the known outcomes are shown here for simplicity. b The antibody trastuzumab binds directly to domain IV of the extracellular region of ERBB2, suppressing ERBB2 signaling activity, preventing cleavage of the extracellular domain, and marking tumor cells that overexpress ERBB2 for further immunological attack through antibody-dependent cell-mediated cytotoxicity. GSK3β, glycogen synthase kinase 3β; NF-κB, nuclear factor-κB; PDK1, pyruvate dehydrogenase kinase 1; PIP2, phosphatidylinositol biphosphate; PIP3, phosphatidylinositol triphosphate
Mentions: The Erbb family consists of four closely related type 1 transmembrane tyrosine kinase receptors: EGFR (or HER1), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). Each receptor comprises an extracellular domain at which ligand binding occurs, an α-helical transmembrane segment, and an intracellular protein tyrosine kinase domain. Ligand binding to these EGF family receptors phosphorylates and activates a complex intracellular signaling pathways network that controls a range of cellular processes including proliferation, angiogenesis, cell cycle, survival, and apoptosis (Fig. 1a).3Fig. 1

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

A new molecular classification and novel targeted therapy can improve poor oncological outcomes of some patients with gastric cancer... Each year 900,000 patients are diagnosed worldwide with gastric cancer... Potentially, approximately 25% of these patients may benefit by adding trastuzumab to current standard treatment... Inhibition of signaling cascades may suppress cancer cell proliferation and survival... However, for most solid tumors, clinical efficacy measured by overall survival benefit is modest... Phase III trials confirming preclinical and clinical data for the safety and efficacy of trastuzumab independently of robust clinicopathologic factors in both metastatic and adjuvant setting have led to the establishment of this antibody as standard treatment for HER2-positive breast cancer. – However, there has been no such evidence for any other cancer... Based on a pivotal phase III study, lapatinib in combination with capecitabine has been approved by the FDA for use in patients with advanced HER2-positive breast cancer who have previously received trastuzumab... Therefore, lapatinib alone or in combination with trastuzumab, which was shown to be superior to a single agent, are potential effective therapies to overcome trastuzumab resistance in HER2-positive gastric cancer... Given the current strong evidence that multiple genetic alterations and several signaling pathways are dysregulated in solid cancers, one of the most rational approaches is to inhibit these pathways... Combining targeted agents and considering crosstalk between pathways and bypass of targeted agents as well as predictors of response might lead to highly effective therapies... Rapid advances in molecular systems biology and future cheaper whole-genome cancer data scans are innovative exciting developments towards the development of novel response predictors and a new generation of multitargeted agents., The new era of personalized cancer care is here, but multiple challenges including major funding requirements and reliable data analysis make the translation of personalized research approaches into clinical medical practice difficult... Addition of trastuzumab to chemotherapy improves overall survival and is a new standard treatment for patients with locally advanced, recurrent or metastatic HER2-positive disease... Lapatinib and other novel antibodies or TKIs tested in clinical trials for HER2-positive breast cancer might also prove effective in trastuzumab-resistant HER2-positive gastric cancer... Understanding genotypic–phenotypic cancer diversity and signaling feedback loops as well as developing reliable methods to screen for identifying dysregulated signaling pathways in individual patients is a rational and exciting approach... If successful, such comprehensive approaches using molecular systems biology and future whole-genome cancer data scans may result in the discovery of novel multitargeted therapies tailored to individual patients on the basis of novel predictors of response to combined therapies.

Show MeSH
Related in: MedlinePlus