Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In 2006 there were 60,000 new cases of cutaneous melanoma in the European Union and 13,000 deaths (www.europeancancerleagues. org). Currently available systemic treatment options for metastatic melanoma, including both cytotoxic and immunologic therapies, produce low rates of response and have modest survival impact. Therefore, there is an urgent need for effective novel therapies. Molecularly targeted treatments have demonstrated efficacy in certain cancers e.g. in HER2- positive breast cancer and in chronic myeloid leukaemia. Several pathways are currently being investigated as potential molecular targets in melanoma. The best studied is BRAF which is frequently mutated in melanoma. A multi tyrosine kinase inhibitor, sorafenib, which targets BRAF, has shown promising activity in preclinical studies and is currently being tested in combination with chemotherapy in patients with metastatic disease. In addition to BRAF, therapies which target other components of the Raf/Ras/MAPK pathway are being investigated. Other novel targets currently being investigated include the PI3/AKT pathway, tyrosine kinases, angiogenesis, poly (ADP ribose) polymerases, survivin and heat shock protein 90. Progress on preclinical and clinical evaluation of these novel targets in melanoma will be reviewed.
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PMID:Prospects for non-immunological molecular therapeutics in melanoma. 2041 21

Anorectal melanomas (AMs) are very rare and highly malignant tumors that are often diagnosed in advanced stages. After the differentiation between cutaneous melanoma (CM) and AM on the molecular level based on the presence of BRAF mutations, further modes of differentiation opened up, such as the recently discovered immunohistologically relevant protein deleted in malignant brain tumors 1 (DMBT1). Over the past several years, increasingly specific therapies have been developed on the basis of new therapy principles. Tyrosin kinase receptors such as Her2 and EGFR have been awarded a large role in this context. The goal of this study was to examine AMs for a possible expression or overexpression of these markers. Expression analyses of Her2 and EGFR were performed immunohistologically on 25 primary AMs. An overexpression of Her2 (score: 3+) was found in one AM from a 68-year-old female patient among these samples. In contrast, EGFR expression was not found in any of the AMs. The results presented here show that isolated cases of AM may benefit from an additive Her2-directed therapy, as the overexpression of Her2 was found in one of our AM patients.
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PMID:Her2 overexpression is a rare event in anorectal melanoma. 2056 56

Primary malignant melanoma of esophagus (PMME) is a rare tumor; therefore, the prognostic factors, predictive factors, and difference in biological behaviors of cutaneous melanoma and primary esophageal squamous cell carcinoma remain uncertain. Although we did not adopt a standard therapeutic strategy, we performed surgical resection, chemotherapy, immunotherapy, and radiotherapy either alone or in combination; all procedures resulted in poor outcomes. A 67-year-old woman presented with a swallowing disorder. An esophagogastroduodenoscopy was performed, leading to diagnosis of PMME. According to the Japanese Classification of Esophageal Cancer, the pathological stage was T1b, ly0, v0, N0, M0, stage I . KIT immunostaining was focally positive. After subtotal esophagectomy, adjuvant chemotherapy was performed, but the malignant melanoma relapsed in the mediastinum and the patient died 10 months after diagnosis. We serially monitored the patient using several new modalities, including PET/CT, metabolites of melanin: 5-S-CD, and circulating tumor cells (CTCs) by reverse transcription-polymerase chain reaction to identify the melanoma-specific gene. To our knowledge, this is the first report of a case in which CTCs in PMME were detected.
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PMID:[Primary malignant melanoma of the esophagus--detection of circulating tumor cells]. 2071 82

The majority of melanomas show constitutive activation of the RAS-RAF-MAP/ERK kinase (MEK)-mitogen-activated protein kinase (MAPK) pathway. AZD6244 is a selective MEK1/2 inhibitor that markedly reduces tumor P-MAPK levels, but it produces few clinical responses in melanoma patients. An improved understanding of the determinants of resistance to AZD6244 may lead to improved patient selection and effective combinatorial approaches. The effects of AZD6244 on cell growth and survival were tested in a total of 14 Braf-mutant and 3 wild-type human cutaneous melanoma cell lines. Quantitative assessment of phospho-protein levels in the Braf-mutant cell lines by reverse phase protein array (RPPA) analysis showed no significant association between P-MEK or P-MAPK levels and AZD6244 sensitivity, but activation-specific markers in the phosphoinositide 3-kinase (PI3K)-AKT pathway correlated with resistance. We also identified resistant cell lines without basal activation of the PI3K-AKT pathway. RPPA characterization of the time-dependent changes in signaling pathways revealed that AZD6244 produced durable and potent inhibition of P-MAPK in sensitive and resistant Braf-mutant cell lines, but several resistant lines showed AZD6244-induced activation of AKT. In contrast, sensitive cell lines showed AZD6244 treatment-induced upregulation of PTEN protein and mRNA expression. Inhibition of AKT, TORC1/2, or insulin-like growth factor I receptor blocked AZD6244-induced activation of AKT and resulted in synergistic cell killing with AZD6244. These findings identify basal and treatment-induced regulation of the PI3K-AKT pathway as a critical regulator of AZD6244 sensitivity in Braf-mutant cutaneous melanoma cells and the novel regulation of PTEN expression by AZD6244 in sensitive cells, and suggest new combinatorial approaches for patients.
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PMID:Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. 2095 81

Melanoma is the most aggressive and deadly type of skin cancer. Surgical resection with or without lymph node sampling is the standard of care for primary cutaneous melanoma. Adjuvant therapy decisions may be informed by careful consideration of prognostic factors. High-dose adjuvant interferon alpha-2b increases disease-free survival and may modestly improve overall survival. Less toxic alternatives for adjuvant therapy are currently under study. External beam radiation therapy is an option for nodal beds where the risk of local recurrence is very high. In-transit melanoma metastases may be treated locally with surgery, immunotherapy, radiation, or heated limb perfusion. For metastatic melanoma, the options include chemotherapy or immunotherapy; targeted anti-BRAF and anti-KIT therapy is under active investigation. Standard chemotherapy yields objective tumor responses in approximately 10%-20% of patients, and sustained remissions are uncommon. Immunotherapy with high-dose interleukin-2 yields objective tumor responses in a minority of patients; however, some of these responses may be durable. Identification of activating mutations of BRAF, NRAS, c-KIT, and GNAQ in distinct clinical subtypes of melanoma suggest that these are molecularly distinct. Emerging data from clinical trials suggest that substantial improvements in the standard of care for melanoma may be possible.
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PMID:Treatment of cutaneous melanoma: current approaches and future prospects. 2118 11

The discovery of BRAF and KIT mutations provided the first basis for a molecular classification of cutaneous melanoma on therapeutic grounds. As BRAF-targeted therapy quickly moves toward regulatory approval and incorporation as standard therapy for patients with metastatic disease, proof of concept has also been established for targeting mutated KIT in melanoma. NRAS mutations have long been known to be present in a subset of melanomas and represent an elusive subgroup for targeted therapies. Matching patient subgroups defined by genetic aberrations in the phosphoinositide 3-kinase and p16/cyclin dependent kinase 4 (CDK4) pathways with appropriate targeted therapies has not yet been realized. And, an increasing understanding of lineage-specific transcriptional regulators, most notably MITF, and how they may play a role in melanoma pathophysiology, has provided another axis to approach with therapies. The foundation has been established for individual oncogene targeting, and current investigations seek to understand the intersection of these susceptibilities and other described potential targets and pathways. The melanoma field stands poised to take the lead among cancer subtypes in advancing combination therapy strategies that simultaneously target multiple biologic underpinnings of the disease.
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PMID:New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances. 2167 85

Oral malignant melanoma (OMM) is a rare condition, and our knowledge about morphological and genetic modifications is scanty and incomplete. The aim of this study is to report morphological and fluorescent in situ hybridisation (FISH) data obtained in four cases of OMM. FISH results were also compared with those of cutaneous malignant melanoma (CMM, three cases), desmoplastic cutaneous melanoma (DMM, four cases) and spindle cells cutaneous melanoma (SCCM, one case). All the OMM cases showed a combined radial and vertical growth pattern, with the invasive component characterised by malignant spindle cells intermingled among collagen bundles. Two cases of OMM resulted positively stained with p16, in contrast with frequent loss of immunoreactivity in CMM. Three OMM were suitable for FISH analysis: 9p21 locus was deleted in 1/3, 1p36 resulted deleted 3/3, while EGFR gene showed a relative deletion. Similar genetic alterations were found in DMM and SCMM, but not in CMM. Ultrastructural findings further enhanced differences between OMM and CMM; OMM displayed, mature-staged melanosomes only within in situ component. In conclusion, OMM presents a morphological and genetic profile similar to DMM; and SCCM, however, displays some differences from CMM.
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PMID:Genetic markers of oral malignant melanoma analysed by fluorescence in situ hybridisation (FISH). 2171 65

Recent evidence suggests that the biology of noncutaneous melanoma differs significantly from cutaneous melanoma and may provide therapeutic opportunity. The most frequent sites of origin of noncutaneous melanoma are the eye and mucosal surfaces. Although noncutaneous melanomas are an uncommon group of cancers (representing less than 10% of all melanomas) a greater understanding of their genetic and molecular abnormalites is being translated into novel treatment strategies. These developments are important because there is currently no effective systemic therapy for noncutaneous melanoma. Significant attention has been focused on the role of c-kit (KIT, CD117), a transmembrane receptor with tyrosine kinase activity. In vitro and ex vivo evidence suggests that c-kit is frequently expressed/over expressed/mutated in noncutaneous melanoma. Anti-tumour effects with c-kit inhibitors are seen in pre-clinical models. A variety of multitargeted kinase inhibitors which have activity against c-kit are currently in early phase clinical trials in metastatic ocular, mucosal and acral melanoma. The few case reports of significant clinical activity with targeted therapies provides hope that greater understanding of the biology of noncutaneous melanoma can be translated into effective treatment.
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PMID:Therapeutic opportunities in noncutaneous melanoma. 2178 11

Cutaneous malignant melanoma is one of the most serious skin cancers and is highly invasive and markedly resistant to conventional therapy. Melanomagenesis is initially triggered by environmental agents including ultraviolet (UV), which induces genetic/epigenetic alterations in the chromosomes of melanocytes. In human melanomas, the RAS/RAF/MEK/ERK (MAPK) and the PI3K/PTEN/AKT (AKT) signaling pathways are two major signaling pathways and are constitutively activated through genetic alterations. Mutations of RAF, RAS, and PTEN contribute to antiapoptosis, abnormal proliferation, angiogenesis, and invasion for melanoma development and progression. To find better approaches to therapies for patients, understanding these MAPK and AKT signaling mechanisms of melanoma development and progression is important. Here, we review MAPK and AKT signaling networks associated with melanoma development and progression.
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PMID:RAS/RAF/MEK/ERK and PI3K/PTEN/AKT Signaling in Malignant Melanoma Progression and Therapy. 2201 35

Cutaneous melanoma is a highly aggressive cancer with still limited, but increasingly efficacious, standard treatment options. Recent preclinical and clinical findings support the notion that cutaneous melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma already has great implications for the management of cutaneous melanoma. Herein, we review our rapidly growing understanding of the molecular biology of cutaneous melanoma, including the pathogenic roles of the mitogen-associated protein kinase (MAPK) pathway, the phosphatidylinositol 3 kinase [PI3K]/phosphatase and tensin homologue deleted on chromosome 10 [PTEN]/Akt/mammalian target of rapamycin [mTOR])PTEN (phosphatase and tensin homolog) pathway, MET (hepatocyte growth factor), Notch signaling, and other key molecules regulating cell cycle progression and apoptosis. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with clinical benefit from agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Cutaneous melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. These findings suggest that prospective genotyping of patients with melanoma, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, should be used increasingly as we work to develop new and more effective treatments for this devastating disease.
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PMID:The molecular pathology of cutaneous melanoma. 2211 80


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