Epidermal growth factor receptor targeting in cancer: a review of trends and strategies.
TL;DR: The role of EGfr in cancer, different types of EGFR inhibitors, preclinical and clinical status of EG FR inhibitors as well as summarized the recent efforts made in the field of molecular EGFR targeting are outlined.
About: This article is published in Biomaterials.The article was published on 2013-11-01. It has received 409 citations till now. The article focuses on the topics: EGFR inhibitors & Gefitinib.
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TL;DR: An overview of key components of the immune infiltrating cells in the tumor microenvironment is provided, reviewing immunological principles related to head and neck cancer, including the concept of cancer immunosurveillance and immune escape.
Abstract: The immune system plays a key role in the development, establishment, and progression of head and neck squamous cell carcinoma (HNSCC). A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of HNSCC provides the basis for improved therapies and outcomes for patients. HNSCC cells evade the host immune system through manipulation of their own immunogenicity, production of immunosuppressive mediators, and promotion of immunomodulatory cell types. Through the tumor's influence on the microenvironment, the immune system can be exploited to promote metastasis, angiogenesis, and growth. This article provides a brief overview of key components of the immune infiltrating cells in the tumor microenvironment, reviewing immunological principles related to head and neck cancer, including the concept of cancer immunosurveillance and immune escape. Current immunotherapeutic strategies and emerging results from ongoing clinical trials are presented.
498 citations
TL;DR: This Review discusses issues and recent advances in understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration.
Abstract: More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin-proteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration
480 citations
TL;DR: In this paper, a review aimed at reporting recent strategies to develop innovative organic photosensitizers for enhanced photodynamic therapy, with each example described in detail instead of providing only a general overview, to provide intuitive, vivid, and specific insights to the readers.
Abstract: This review presents a robust strategy to design photosensitizers (PSs) for various species. Photodynamic therapy (PDT) is a photochemical-based treatment approach that involves the use of light combined with a light-activated chemical, referred to as a PS. Attractively, PDT is one of the alternatives to conventional cancer treatment due to its noninvasive nature, high cure rates, and low side effects. PSs play an important factor in photoinduced reactive oxygen species (ROS) generation. Although the concept of photosensitizer-based photodynamic therapy has been widely adopted for clinical trials and bioimaging, until now, to our surprise, there has been no relevant review article on rational designs of organic PSs for PDT. Furthermore, most of published review articles in PDT focused on nanomaterials and nanotechnology based on traditional PSs. Therefore, this review aimed at reporting recent strategies to develop innovative organic photosensitizers for enhanced photodynamic therapy, with each example described in detail instead of providing only a general overview, as is typically done in previous reviews of PDT, to provide intuitive, vivid, and specific insights to the readers.
391 citations
TL;DR: The ability to target receptor tyrosine kinases for degradation using the PROTAC technology is demonstrated and the advantages of this degradation-based approach are outlined.
369 citations
TL;DR: The role of E-cadherin and its downstream signaling in regulation of contact inhibition and the development and progression of cancer are discussed.
Abstract: E-cadherin is a key component of the adherens junctions that are integral in cell adhesion and maintaining epithelial phenotype of cells. Homophilic E-cadherin binding between cells is important in mediating contact inhibition of proliferation when cells reach confluence. Loss of E-cadherin expression results in loss of contact inhibition and is associated with increased cell motility and advanced stages of cancer. In this review we discuss the role of E-cadherin and its downstream signaling in regulation of contact inhibition and the development and progression of cancer.
289 citations
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TL;DR: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib, and these mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor.
Abstract: BACKGROUND Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.
10,879 citations
"Epidermal growth factor receptor ta..." refers background in this paper
...Approximately 10% of NSCLC patients were found to respond to gefitinib therapy [106]....
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TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
7,056 citations
TL;DR: When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signalling pathways, culminating in responses ranging from cell division to death, motility to adhesion.
Abstract: When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signalling pathways, culminating in responses ranging from cell division to death, motility to adhesion. The network is often dysregulated in cancer and lends credence to the mantra that molecular understanding yields clinical benefit: over 25,000 women with breast cancer have now been treated with trastuzumab (Herceptin), a recombinant antibody designed to block the receptor ErbB2. Likewise, small-molecule enzyme inhibitors and monoclonal antibodies to ErbB1 are in advanced phases of clinical testing. What can this pathway teach us about translating basic science into clinical use?
6,462 citations
"Epidermal growth factor receptor ta..." refers background in this paper
...[56] and excessive EGFR waving can arise from receptor overexpression, autocrine signaling or mutation....
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University of Alabama at Birmingham1, University of Wisconsin-Madison2, Autonomous University of Barcelona3, Eli Lilly and Company4, University of Texas MD Anderson Cancer Center5, University of Virginia6, University of the Witwatersrand7, University of Colorado Boulder8, Gdańsk Medical University9, University of Alabama10, Merck KGaA11, ImClone Systems12
TL;DR: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoreGional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head andneck.
Abstract: BACKGROUND We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P = 0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P = 0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P = 0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant highdose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)
4,705 citations
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...effects associated with radiotherapy [173]...
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TL;DR: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with ir inotecans-refractory colorectal cancer.
Abstract: background The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. methods We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. results The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combinationtherapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. conclusions Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.
4,625 citations