Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The RAS-RAF-MEK1/2-ERK1/2 pathway is a key signal transduction pathway in the cells. Critically, it remains constitutively active in approximately 30% of human cancers, having key roles in cancer development, maintenance and progression, while being responsible for poorer prognosis and drug resistance. Consequently, the inhibition of this pathway has been the subject of intense research for >25 years. The advent of better patient screening techniques has increasingly shown that upstream regulators like RAS and RAF remain persistently mutated in many cancer types. These gain-of-function mutations, such as KRAS-4B(G12V/G13D/Q61K), NRAS(Q61L/Q61R) or BRAF(V600E), lead to tremendous increase in their activities, resulting in constitutively active extracellular signal-regulated kinase 1/2 (ERK1/2). They were not efficiently targeted by the first-generation inhibitors such as Lonafarnib or Sorafenib, which were essentially broad spectrum inhibitors targeting pan-RAS and pan-RAF, respectively. This triggered the development of the second-generation inhibitors selective against the mutated proteins. Second generation inhibitors such as Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar) targeting BRAF(V600E), Trametinib (Mekinist) targeting MEK1/2 and the first generation pan-RAF inhibitor Sorafenib (Nexavar) have already been approved for treating renal, hepatocellular, thyroid cancers and BRAF(V600E/K) harboring metastatic melanoma. Others against RAF and MEK1/2 are presently undergoing clinical trials. Their success would depend on the better understanding of the acquired resistance mechanisms to these drugs in the cancer cells and the identification of predictive biomarkers for the proper administration of suitable inhibitor(s).
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PMID:Stamping out RAF and MEK1/2 to inhibit the ERK1/2 pathway: an emerging threat to anticancer therapy. 2636 6

Melanoma lacks a clinically useful blood-based biomarker of disease activity to help guide patient management. To determine whether measurements of circulating, cell-free, tumor-associated BRAF(mutant) and NRAS(mutant) DNA (ctDNA) have a higher sensitivity than LDH to detect metastatic disease prior to treatment initiation and upon disease progression we studied patients with unresectable stage IIIC/IV metastatic melanoma receiving treatment with BRAF inhibitor therapy or immune checkpoint blockade and at least 3 plasma samples obtained during their treatment course. Levels of BRAF(mutant) and NRAS(mutant) ctDNA were determined using droplet digital PCR (ddPCR) assays. Among patients with samples available prior to treatment initiation ctDNA and LDH levels were elevated in 12/15 (80%) and 6/20 (30%) (p = 0.006) patients respectively. In patients with RECIST scores <5 cm prior to treatment initiation, ctDNA levels were elevated in 5/7 (71%) patients compared to LDH which was elevated in 1/13 (8%) patients (p = 0.007). Among all disease progression events the modified bootstrapped sensitivities for ctDNA and LDH were 82% and 40% respectively, with a median difference in sensitivity of 42% (95% confidence interval, 27%-58%; P < 0.001). In addition, ctDNA levels were elevated in 13/16 (81%) instances of non-RECIST disease progression, including 10/12 (83%) instances of new brain metastases. In comparison LDH was elevated 8/16 (50%) instances of non-RECIST disease progression, including 6/12 (50%) instances of new brain metastases. Overall, ctDNA had a higher sensitivity than LDH to detect disease progression, including non-RECIST progression events. ctDNA has the potential to be a useful biomarker for monitoring melanoma disease activity.
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PMID:Sensitivity of plasma BRAFmutant and NRASmutant cell-free DNA assays to detect metastatic melanoma in patients with low RECIST scores and non-RECIST disease progression. 2644 Jul 7

Metastatic malignant melanoma is notorious for its phenotypic diversity and loss of differentiation markers. We herein summarized our experience with 14 metastatic melanomas showing complete loss of immunohistochemical melanocytic markers (with or without heterologous differentiation). Patients included 11 men and 3 women aged 24 to 78 years (median, 67 y). Thirteen patients had histologically confirmed primary skin melanoma, and 1 had metastatic melanoma of unknown primary. Undifferentiated metastasis was diagnosed synchronous to primary tumor (n=1), following skin melanoma by 3 months to 9 years (n=11) and preceding it by 1 year (n=1). Sites of undifferentiated metastases were axillary (3), inguinal (1), or submandibular (1) lymph nodes, digestive tract (2), bone/soft tissue (2), lung/pleura (2), and disseminated (n=3). Histology of metastases mimicked undifferentiated pleomorphic or spindle cell sarcoma with variable myxoid and giant cell areas (n=10) and cytokeratin-positive undifferentiated small cell sarcoma (n=1). Three cases showed heterologous dedifferentiation: pleomorphic rhabdomyosarcoma (n=1), teratocarcinosarcoma-like with prominent rhabdomyoblasts (n=1), and adenocarcinoma-like with metaplastic bone (n=1). All cases were negative for S100, melanoma cocktail, HMB45, Melan A, and SOX10. Other markers showed following results: smooth muscle actin (1/14), p16 (1/14), TP53 (2/12), pancytokeratin (4/14), desmin (5/14), h-caldesmon (0/9), and MDM2/CDK4 (0/5). SMARCB1 was intact in 8/8 cases. Genotyping showed BRAF(V600E) mutation (5/14), NRAS mutation (5/14), and BRAF/NRAS wild-type (4/14). In conclusion, undifferentiated/dedifferentiated metastatic melanoma is likely underrecognized and frequently mistaken for undifferentiated sarcoma or other neoplasms. Diagnosis of undifferentiated sarcoma at sites where melanoma metastasis are frequent (eg, inguinal and axillary region) should be made with great caution and warrants exploration of the remote history. Genotyping is a helpful surrogate marker in classifying such difficult cases. In the light of available targeted therapies, recognition of undifferentiated/dedifferentiated metastatic melanoma is mandatory for appropriate treatment.
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PMID:Metastatic Malignant Melanoma With Complete Loss of Differentiation Markers (Undifferentiated/Dedifferentiated Melanoma): Analysis of 14 Patients Emphasizing Phenotypic Plasticity and the Value of Molecular Testing as Surrogate Diagnostic Marker. 2703 13

Melanoma is a malignancy of pigment-producing cells that is driven by a variety of genetic mutations and aberrations. In most cases, this leads to upregulation of the mitogen-activated protein kinase (MAPK) pathway through activating mutations of upstream mediators of the pathway including BRAF and NRAS. With the advent of effective MAPK pathway inhibitors, including the US FDA-approved BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib, molecular analysis has become an integral part of the care of patients with metastatic melanoma. In this article, the key molecular targets and strategies to inhibit these targets therapeutically are presented, and the techniques of identifying these targets, in both tissue and blood, are discussed.
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PMID:The Future of Molecular Analysis in Melanoma: Diagnostics to Direct Molecularly Targeted Therapy. 2651 80

Repeat tumor biopsies to study genomic changes during therapy are difficult, invasive and data are confounded by tumoral heterogeneity. The analysis of circulating tumor DNA (ctDNA) can provide a non-invasive approach to assess prognosis and the genetic evolution of tumors in response to therapy. Mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF and NRAS variants in 48 patients with advanced metastatic melanoma prior to treatment with targeted therapies (vemurafenib, dabrafenib or dabrafenib/trametinib combination) or immunotherapies (ipilimumab, nivolumab or pembrolizumab). Baseline ctDNA levels were evaluated relative to treatment response and progression-free survival (PFS). Tumor-associated ctDNA was detected in the plasma of 35/48 (73%) patients prior to treatment and lower ctDNA levels at this time point were significantly associated with response to treatment and prolonged PFS, irrespective of therapy type. Levels of ctDNA decreased significantly in patients treated with MAPK inhibitors (p < 0.001) in accordance with response to therapy, but this was not apparent in patients receiving immunotherapies. We show that circulating NRAS mutations, known to confer resistance to BRAF inhibitors, were detected in 3 of 7 (43%) patients progressing on kinase inhibitor therapy. Significantly, ctDNA rebound and circulating mutant NRAS preceded radiological detection of progressive disease. Our data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors.
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PMID:Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma. 2652 82

Melanoma of unknown primary (MUP) is a type of metastatic melanoma with no evidence of a primary tumor. Recent evidence suggested better survival in MUP as compared to melanoma with a known primary site (MKP). However, prognostic markers that reliably predict overall survival in MUP are lacking. The primary objective of this study was to analyze the mutational status of the BRAF, NRAS, and KIT oncogenes and to investigate if the genotype or other clinical parameters were associated with overall survival. We retrospectively analyzed the genotype and the clinical course of 40 patients with MUP. Mutations of BRAF and NRAS were determined with pyrosequencing. Mutations of KIT were investigated with a nested PCR approach followed by Sanger sequencing. Survival fractions were calculated applying the Kaplan-Meier model. Mutations in the BRAF (50.0%), NRAS (17.5%), and KIT genes (5.0%) were found frequently, but had no major impact on overall survival (p=0.62). The AJCC stage was a strong prognostic factor with a hazard ratio for death of 0.17 (stage III vs. IV; p=0.04). All patients diagnosed with stage III disease survived the median follow-up period of 23 months (p=0.03). The survival rates of patients with stage IV were significantly associated with rapid disease progression but not with metastatic tumor load at primary diagnosis (p=0.01). Altogether, AJCC stage and time to disease progression were important prognostic parameters. We propose that the kinetics of the disease but not the initial metastatic burden nor the mutational status is relevant for survival in advanced MUP.
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PMID:Disease kinetics but not disease burden is relevant for survival in melanoma of unknown primary tumor. 2656 76

The role of the Pax3 gene in embryonic development of pigment cells is well characterized. By contrast, the function of Pax3 in melanoma development is controversial. Indeed, data obtained from cultured cells suggest that PAX3 may contribute to melanomagenesis. PAX3 is found to be overexpressed in melanomas and also in nevi compared with normal skin samples. Pax3 homozygous loss of function is embryonic lethal. To assess the role of Pax3 in melanoma development in vivo, we analyzed Pax3 haploinsufficiency in a mouse model of melanoma predisposition. The Pax3(GFP/+) knock-in reporter system was combined with the Tyr::NRAS(Q61K); Cdkn2a(-/-) mouse melanoma model. Melanoma development was followed over 18 months. Histopathological, immunohistochemical, and molecular analyses of lesions at different stages of melanoma progression were carried out. Fluorescence-activated cell sorting on GFP of cells from primary or metastatic melanoma was followed by ex-vivo transformation tests and in-vivo passaging. We report here that Tyr::NRAS(Q61K); Cdkn2a(-/-); Pax3(GFP/+) mice developed metastasizing melanoma as their Tyr::NRAS(Q61K); Cdkn2a(-/-); littermates. Histopathology showed no differences between the two genotypes, although Pax3 mRNA and PAX3 protein levels in Pax3(GFP/+) lesions were reduced by half. The Pax3(GFP) allele proved to be a convenient marker to identify and directly sort heterogeneous populations of melanoma cells within the tumor bulk at each stage of melanoma progression. This new mouse model represents an accurate and reproducible means for identifying melanoma cells in vivo to study the mechanisms of melanoma development.
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PMID:Haplosufficiency of PAX3 for melanoma development in Tyr: NRASQ61K; Cdkn2a-/- mice allows identification and sorting of melanoma cells using a Pax3GFP reporter allele. 2658 92

Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma.
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PMID:Phytochemicals for the Management of Melanoma. 2895 29

A number of common driver mutations have been identified in melanoma, but other genetic or epigenetic aberrations are also likely to play a role in the pathogenesis of melanoma and present potential therapeutic targets. Translocations of the anaplastic lymphoma kinase (ALK), for example, have been reported in spitzoid melanocytic neoplasms leading to kinase-fusion proteins that result in immunohistochemically detectable ALK expression. In this study, we sought to determine whether ALK was also expressed in nonspitzoid primary and metastatic cutaneous melanomas. ALK immunohistochemistry was performed on 603 melanomas (303 primary and 300 metastatic tumors) from 600 patients. ALK immunohistochemistry expression was identified in 7 primary and 9 metastatic tumors. In 5 of 7 primary tumors and in 6 of 9 metastatic lesions, the majority of tumor cells were immunoreactive for ALK. In the other 2 primary and 3 metastatic lesions, positive staining was identified in less than half of the tumor cells. ALK positivity was found in the presence or absence of BRAF or NRAS mutations. In contrast to prior observations with ALK-positive Spitz tumors, none of the ALK-positive melanomas harbored a translocation. Instead, the ALK-positive melanomas predominantly expressed the recently described ALK isoform, ALK, which lacks the extracellular and transmembrane domains of wild-type ALK, consists primarily of the intracellular tyrosine kinase domain, and originates from an alternative transcriptional initiation site within the ALK gene. The findings are clinically relevant as patients with metastatic melanoma who have ALK expression may potentially benefit from treatment with ALK kinase inhibitors.
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PMID:Primary and Metastatic Cutaneous Melanomas Express ALK Through Alternative Transcriptional Initiation. 2728 52

The aim of personalized medicine is to improve our understanding of the disease at molecular level and to optimize therapeutic management. In this context, we have developed in vivo and ex vivo preclinical strategies evaluating the efficacy of innovative drugs in melanomas. Human melanomas (n = 17) of different genotypes (mutated BRAF, NRAS, amplified cKIT and wild type) were successfully engrafted in mice then amplified by successive transplantations. The exhaustive characterization of patient-derived xenografts (PDX) at genomic level (transcriptomic and CGH arrays) revealed a similar distribution pattern of genetic abnormalities throughout the successive transplantations compared to the initial patient tumor, enabling their use for mutation-specific therapy strategies. The reproducibility of their spontaneous metastatic potential in mice was assessed in 8 models. These PDXs were used for the development of histoculture drug response assays (ex vivo) for the evaluation of innovative drug efficacy (BRAF and MEK inhibitors). The pharmacological effects of BRAF and MEK inhibitors were similar between PDX-derived histocultures and their corresponding PDX, on 2 models of BRAF and NRAS-mutated melanomas. These models constitute a validated, effective tool for preclinical investigation of new therapeutic agents, and improve therapeutic strategies in the treatment of metastatic melanoma.
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PMID:Validation of a preclinical model for assessment of drug efficacy in melanoma. 2788 90


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