Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cetuximab is a monoclonal antibody targeting the transmembrane receptor HER-1 (epidermal growth factor receptor, EGFR). In theory, inhibition of EGFR may influence tumor behavior since the receptor regulates many important tumor cell activities including tumor growth, angiogenesis, and inhibition of the apoptotic response to chemotherapy and radiotherapy. Available experimental data suggest that cetuximab may enhance the activity of chemotherapy and radiotherapy, reverse resistance to some anticancer drugs, and has itself anticancer activity. Early clinical data support the experimental results. This paper reviews the published findings on cetuximab in the treatment of advanced head and neck cancer and points out the future objectives of the clinical research on this drug.
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PMID:Treatment of advanced head and neck cancer with cetuximab. 1752 May 84

The incidence of SCCHN is expected to be approximately 42,800 new cases in the United States with more than 12,000 deaths from this disease for the year 2006. The five-year survival rate for patients with SCCHN in the United States and other developed countries is still poor, approximately 40%, and even those patients who do not experience recurrence of the original cancer, have a high risk of developing a second primary malignancy. Thus, a preventative approach before the development of invasive cancer is highly desirable and novel strategies to reduce cancer incidence in SCCHN and other tobacco-carcinogen related malignancies are being pursued. Ever since the last two decades have seen the rise and fall of the results of clinical trials using carotinoids and retinoids as chemopreventive agents, new treatment strategies are needed. Selective and nonselective COX-1/2 inhibitors and EGFR tyrosine kinase inhibitors have shown promising results in cancer therapy and are currently evaluated in chemoprevention trials. However, associated high costs and side effects make these less attractive to patients with premalignant lesions. Phytochemical containing foods like green tea, pomegranate juice and other natural compounds are attractive since they are less costly, nontoxic and widely available. While small trials have shown promising results using these agents, larger trials have yet to be conducted to establish chemopreventive effects. Since premalignant lesions of the oral cavity are easily accessible for topical treatments, it remains to be seen if there is a role for topical treatments. Current clinical trials using these novel agents for prevention of second primary tumors or treatment of premalignant lesions will further elucidate which agents should be used but also will help to establish the role of chemoprevention in head and neck cancer.
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PMID:Current status and future perspectives of chemoprevention in head and neck cancer. 1804 67

Radiotherapy is an essential treatment for many patients with head and neck squamous cell carcinoma. Its association with molecular targeted therapies represents a real progress. Among the recent advances in the molecular targeted therapy of cancer, the applications centred on EGFR are currently the most promising and the most advanced at clinical level. Considering the set of therapeutic tools targeting EGFR, there are at present two well-identified emerging categories of drugs with monoclonal antibodies, on the one hand, and tyrosine kinase inhibitors, on the other. In many preclinical studies, the combination of anti-EGFR drugs with irradiation has led to additive or supra-additive cytotoxic effects. Furthermore, antiangiogenic agents have shown promising results in association with anti-EGFR drugs and radiotherapy. This research effort has recently produced encouraging clinical results in advanced head and neck cancer with combination of cetuximab (an anti-EGFR monoclonal antibody) with irradiation with a significant impact on patient survival. Active and efficient clinical research is currently ongoing to determine the place of molecular targeted therapies in the treatment of head and neck cancer, particularly in association with radiotherapy.
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PMID:[Chemoradiotherapy in head and neck squamous cell carcinoma: focus on targeted therapies]. 1824 34

A common aim of pharmacogenomic studies that use genome-wide assays on panels of cancers is the unbiased discovery of genomic alterations that are associated with clinical outcome and drug response. Previous studies of lapatinib, a selective dual-kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2 tyrosine kinases, have shown predictable relationships between the activity of these target genes and response. Under the hypothesis that additional genes may play a role in drug sensitivity, a predictive model for lapatinib response was constructed from genome-wide DNA copy number data from 24 cancer cell lines. An optimal predictive model which consists of aberrations at nine distinct genetic loci, includes gains of HER2, EGFR, and loss of CDKN2A. This model achieved an area under the receiver operating characteristic curve of approximately 0.85 (80% confidence interval, 0.70-0.98; P < 0.01), and correctly classified the sensitivity status of 8 of 10 head and neck cancer cell lines. This study shows that biomarkers predictive for lapatinib sensitivity, including the previously described copy number gains of EGFR and HER2, can be discovered using novel genomic assays in an unbiased manner. Furthermore, these results show the utility of DNA copy number profiles in pharmacogenomic studies.
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PMID:Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines. 1841 7

Concurrent chemoradiotherapy (CCRT) is one of the standard treatments for advanced head and neck cancer (HNC). Intensive combination chemotherapy has been re-considered for neo-adjuvant chemotherapy in functional preservation protocol. Molecular targeting drugs (MTG) have proved effective for HNC not only in basic study but in many clinical phase II trials. Cetuximab, an anti-EGFR monoclonal antibody, is a key drug for regimens including MTG. Phase III trials with CDDP/carboplatin+5-FU vs CDDP/carboplatin+5-FU+cetuximab proved the combination with cetuximab was statistically effective for survival of patients with recurrent/metastatic HNC. Combination with cetuximab prolonged survival from 7.4 months to 10.1 months in this report. A good response rate and survival rate are reported in phase II study for chemoradiotherapy with CDDP and cetuximab. The three-year overall survival and local control rate were 76% and 71%, respectively. The combination with MTG will be important in CCRT for advanced HNC. It may well be considered the standard treatment for recurrent/metastatic HNC patients in future.
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PMID:[Combination therapy with molecular targeting drugs for head and neck cancer]. 1848 10

Tumor angiogenesis is a hallmark of advanced cancers and an attractive treatment target in multiple solid tumors. In the past 5 years anti-angiogenic therapies have seen a rapid ascent into mainstream clinical practice. For head and neck cancer (HNC), definitive evidence in the form of a pivotal trial is still pending. Nevertheless, preclinical and early clinical data support a central role of angiogenesis for HNC: up to 90% of HNCs express angiogenic factors such as vascular endothelial growth factor (VEGF) and the respective receptors (VEGFR1-3), and multiple studies support the prognostic implications of angiogenic markers for this tumor. Contrary to concerns that anti-angiogenic therapies could increase hypoxia and thereby treatment resistance, anti-angiogenic therapies in preclinical models appear to overcome resistance and preclinically synergize with traditional therapies, eg, radiation. Clinical use of anti-angiogenic agents for HNC, including bevacizumab, sorafenib, sunitinib, and others, is currently limited to clinical trials, and several larger trials are still ongoing. Single-agent anti-angiogenic drugs so far have not shown activity in unselected HNC patients, with a response rate of less than 4% for the small molecule anti-angiogenics sorafenib and the investigational agent SU5416. On the other hand, combinations of anti-angiogenic drugs with other treatments (analogous to other solid tumors) appear promising; for example, the combination of bevacizumab with the EGFR inhibitor erlotinib showed a response rate of 14.6%. Studies of bevacizumab with chemotherapy (phase III Eastern Cooperative Oncology Group [ECOG] trial) and in combination with chemoradiation are currently ongoing. The side effect profile is comparable to what has been observed in other tumor types and include hypertension, proteinuria, and thrombotic and hemorrhagic events. With the intense research effort preclinically and clinically, and some encouraging early results, anti-angiogenic therapies and biomarkers appear to be poised to play an important role in the treatment of HNC in the near future.
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PMID:Targeting angiogenesis in head and neck cancer. 1854 42

Morphology and function of human organs and tissues are well maintained in the improved SCID (severe combined immunodeficient) mice for a long period (approximately 3 years). To study the radiation-induced damage on human thyroid gland, human thyroid tissues transplanted to SCID mice were consecutively exposed to X-rays or 137Cs gamma-rays at high and low dose rates for approximately 2 years. Consecutive irradiation resulted in the disappearance of follicles and significant decrease of thyroid hormone secretion. Mutations in p53 and c-kit genes were induced significantly in human thyroid tissues from old head and neck cancer patients (av. 56.8 years, 4 males) and a Graves' disease patient (20 years, male) over the dose of 24 Gy (44.7+/-5.9 Gy, mean+/-S.E) and 11 Gy (20.2+/-7.8 Gy), respectively, while mutations were not detected at lower doses nor in unexposed matched controls (p < 0.01). There were significant differences in mutation frequency in the transplanted human thyroid tissues (31 years, female) between high dose rate (1.19 Gy/min; 8 in 20 tissues) and low dose rate (0.00023 Gy/min; 0 in 14 tissues) exposures (p < 0.01). Mutations were not detected in RET, K-ras and beta-catenin genes. Expression analysis by GeneChip indicated that gene expression was also well maintained in the transplanted human thyroid tissues. However, lower doses (1 or 3 Gy) of 137Cs gamma-rays can induce changes in gene expression in the transplanted human thyroid tissues. Furthermore, fatally irradiated SCID mice could survive with human bone marrow cell transplantation. When about half of mouse bone marrows were replaced by human bone marrow cells, the human bone marrow cells showed high sensitivity to gamma-irradiation; 28.0% and 0.45% survival after 0.5 and 2.0 Gy exposures, respectively.
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PMID:Differential radiation sensitivity to morphological, functional and molecular changes of human thyroid tissues and bone marrow cells maintained in SCID mice. 1877 92

Despite abundant literature on the use of PET in head and neck cancer, a little is known about the visualization of small laryngeal cancer. Moreover, most literature deals with the radiopharmaceutical (18)F-fludeoxyglucose (FDG), whereas only a few papers address the use of (11)C labeled amino acids. This study was performed to evaluate the feasibility of (11)C-labeled methionine in visualizing small laryngeal cancer. Ten patients with a de novo small laryngeal cancer (7 T1, 3 T2) underwent a MET PET at least 3 weeks after biopsy but prior to further treatment. Static scans were made in 'whole body' mode, covering the head from the external auditory meatus downwards to the whole thorax. The resulting images were judged by experienced specialists in nuclear medicine, who assessed the relative visibility of each tumor on a 3-point scale. Nine tumors were visualized (5 clearly, 4 moderately). One (T1) was not visualized. Small laryngeal cancer can be visualized with (11)C-methionine PET.
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PMID:Visualization of small glottic laryngeal cancer using methyl-labeled 11C-methionine positron emission tomography. 1914 93

Recent advances in genomics, proteomics, bioinformatics and systems biology have unraveled the complex aberrant signaling networks in cancer. The knowledge accrued has dramatically increased the opportunities for discovery of novel molecular targets for drug development. Major emphasis is being laid on designing new therapeutic strategies targeting multiple signaling pathways for more effective disease management. However, the translation of in vitro findings to patient management often poses major challenges that limit their clinical efficacy. Here we will discuss how understanding the dysregulated signaling networks can explain the pitfalls in translating the laboratory findings from the bench-to-bedside and suggest novel approaches to overcome these problems using head and neck cancer as a prototype. The five year survival rates of HNSCC patients (about 50% at 5 years) have not improved significantly despite advancements in multimodality therapy including surgery, radiation and chemotherapy. Molecular targeted therapies with inhibitors of EGFR and VEGF either alone, or in combination with conventional treatments have shown limited improved efficacy. The key deregulated signaling pathways in head and neck squamous cell carcinoma (HNSCC) include EGFR, Ras, TGFbeta, NFkappaB, Stat, Wnt/beta-catenin and PI3-K/AKT/mTOR. The aberrant activities of these interrelated signaling pathways contribute to HNSCC development. In depth understanding of the cross-talks between these pathways and networks will form the basis of developing novel strategies for targeting multiple molecular components for more effective prevention and treatment of HNSCC.
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PMID:Overview of current and future biologically based targeted therapies in head and neck squamous cell carcinoma. 1928 26

Recurrent/metastatic head and neck cancer remains a devastating disease with insufficient treatment options. We investigated the MET receptor tyrosine kinase as a novel target for the treatment of head and neck squamous cell carcinoma (HNSCC). MET/phosphorylated MET and HGF expression was analyzed in 121 tissues (HNSCC/normal) by immunohistochemistry, and in 20 HNSCC cell lines by immunoblotting. The effects of MET inhibition using small interfering RNA/two small-molecule inhibitors (SU11274/PF-2341066) on signaling, migration, viability, and angiogenesis were determined. The complete MET gene was sequenced in 66 head and neck cancer tissue samples and eight cell lines. MET gene copy number was determined in 14 cell lines and 23 tumor tissues. Drug combinations of SU11274 with cisplatin or erlotinib were tested in SCC35/HN5 cell lines. Eighty-four percent of the HNSCC samples showed MET overexpression, whereas 18 of 20 HNSCC cell lines (90%) expressed MET. HGF overexpression was present in 45% of HNSCC. MET inhibition with SU11274/PF-2341066 abrogated MET signaling, cell viability, motility/migration in vitro, and tumor angiogenesis in vivo. Mutational analysis of 66 tumor tissues and 8 cell lines identified novel mutations in the semaphorin (T230M/E168D/N375S), juxtamembrane (T1010I/R988C), and tyrosine kinase (T1275I/V1333I) domains (incidence: 13.5%). Increased MET gene copy number was present with >10 copies in 3 of 23 (13%) tumor tissues. A greater-than-additive inhibition of cell growth was observed when combining a MET inhibitor with cisplatin or erlotinib and synergy may be mediated via erbB3/AKT signaling. MET is functionally important in HNSCC with prominent overexpression, increased gene copy number, and mutations. MET inhibition abrogated MET functions, including proliferation, migration/motility, and angiogenesis. MET is a promising, novel target for HNSCC and combination approaches with cisplatin or EGFR inhibitors should be explored.
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PMID:The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. 1931 76


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