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https://www.readbyqxmd.com/read/28634084/drug-delivery-to-melanoma-brain-metastases-can-current-challenges-lead-to-new-opportunities
#1
Gautham Gampa, Shruthi Vaidhyanathan, Jann N Sarkaria, William F Elmquist
Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease...
June 17, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28630054/slc45a2-a-melanoma-antigen-with-high-tumor-selectivity-and-reduced-potential-for-autoimmune-toxicity
#2
Jungsun Park, Amjad H Talukder, Seonah Lim, Kwanghee Kim, Ke Pan, Brenda Melendez, Sherille D Bradley, Kyle Jackson, Jahan S Khalili, Junmei Wang, Caitlin Creasy, Bih-Fang Pan, Scott E Woodman, Chantale Bernatchez, David Hawke, Patrick Hwu, Kyung-Mi Lee, Jason Roszik, Gregory Lizee, Cassian Yee
Cytotoxic T lymphocyte (CTL)-based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma.  Although the melanocyte differentiation antigens (MDAs) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets...
June 19, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28623774/discrepancy-in-braf-status-among-patients-with-metastatic-malignant-melanoma-a-meta-analysis
#3
REVIEW
Antonis Valachis, Gustav J Ullenhag
The incidence of malignant melanoma is growing rapidly. Approximately half of the cases are BRAF mutated, making treatment with kinase inhibitors a (MEK and BRAF inhibitors) preferred choice in the advanced setting. The vast majority of these patients will benefit from the treatment. It is therefore of vital importance that the BRAF analysis is reliable and reflects the true nature of the tumour. Intraindividual tumour BRAF heterogeneity may exist, and changes of BRAF status over time might occur. We reviewed the literature by searching the PubMed database and 630 potentially relevant studies were identified...
June 14, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28620782/role-of-key-genetic-mutations-on-increasing-migration-of-brain-cancer-cells-through-confinement
#4
Loan Bui, Sayem H Bhuiyan, Alissa Hendrick, Cheng-Jen Chuong, Young-Tae Kim
Uncontrolled invasive cancer cell migration is among the major challenges for the treatment and management of brain cancer. Although the genetic profiles of brain cancer cells have been well characterized, the relationship between the genetic mutations and the cells' mobility has not been clearly understood. In this study, using microfluidic devices that provide a wide range of physical confinements from 20 × 5 μm(2) to 3 × 5 μm(2) in cross sections, we studied the effect of physical confinement on the migratory capacity of cell lines with different types of mutations...
September 2017: Biomedical Microdevices
https://www.readbyqxmd.com/read/28620126/impact-of-phosphoinositide-3-kinase-and-vitamin-d3-nuclear-receptor-single-nucleotide-polymorphisms-on-the-outcome-of-malignant-melanoma-patients
#5
Francesca Morgese, Davide Soldato, Silvia Pagliaretta, Riccardo Giampieri, Donatella Brancorsini, Mariangela Torniai, Silvia Rinaldi, Agnese Savini, Azzurra Onofri, Marina Scarpelli, Rossana Berardi
BACKGROUND: Several studies associating single nucleotide polymorphisms (SNPs) frequencies with tumors outcome have been conducted, nevertheless malignant melanoma literature data are inconclusive.Therefore we evaluate the impact of different genotypes for phosphoinositide-3-kinase (PI3K) and vitamin D3 nuclear receptor (VDR) SNPs on melanoma patients' outcome. MATERIALS AND METHODS: Genomic DNA of 88 patients was extracted from blood and tumor samples. SNPs were determined by PCR using TaqMan assays...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28618197/analysis-of-mutant-allele-fractions-in-driver-genes-in-colorectal-cancer-biological-and-clinical-insights
#6
Rodrigo Dienstmann, Elena Elez, Guillem Argiles, Ignacio Matos, Enrique Sanz-Garcia, Carolina Ortiz, Teresa Macarulla, Jaume Capdevila, Maria Alsina, Tamara Sauri, Helena Verdaguer, Marta Vilaro, Fiorella Ruiz-Pace, Cristina Viaplana, Ariadna Garcia, Stefania Landolfi, Hector G Palmer, Paolo Nuciforo, Jordi Rodon, Ana Vivancos, Josep Tabernero
Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Out of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors) or PIK3CA mutations (PI3K pathway inhibitors)...
June 15, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28614138/acute-exudative-paraneoplastic-polymorphous-vitelliform-maculopathy-during-vemurafenib-and-pembrolizumab-treatment-for-metastatic-melanoma
#7
Harpal S Sandhu, Anton M Kolomeyer, Marisa K Lau, Carol L Shields, Lynn M Schuchter, Charles W Nichols, Tomas S Aleman
PURPOSE: To describe a patient with BRAF mutation-positive cutaneous melanoma who developed acute exudative polymorphous vitelliform maculopathy during vemurafenib and pembrolizumab treatment for metastatic melanoma. METHODS: Retrospective case report documented with wide-field fundus imaging, spectral domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: A 55-year-old woman with bilateral ductal breast carcinoma and BRAF mutation-positive metastatic cutaneous melanoma complained of bilateral blurred vision within 5 days of starting vemurafenib (BRAF inhibitor)...
June 13, 2017: Retinal Cases & Brief Reports
https://www.readbyqxmd.com/read/28612614/-malignant-melanoma-from-classical-histology-towards-molecular-genetic-testing
#8
A Ryška, O Horký, J Berkovcová, I Tichá, M Kalinová, M Matějčková, Á Bóday, J Drábek, P Martínek, J Šimová, K Sieglová, H Vošmiková
BACKGROUND: Malignant melanoma is - in comparison with other skin tumors - a relatively rare malignant neoplasm with highly aggressive biologic behavior and variable prognosis. Recent data in pathology and molecular diagnostics indicate that malignant melanoma is in fact not a single entity but a group of different neoplasms with variable etiopathogenesis, biologic behavior and prognosis. New therapeutic options using targeted treatment blocking MAPK signaling pathway require testing of BRAF gene mutation status...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/28611627/panniculitis-associated-with-mek-inhibitor-therapy-an-uncommon-adverse-effect
#9
Miruna Negulescu, Florian Deilhes, Vincent Sibaud, Emilie Tournier, Laurence Lamant, Serge Boulinguez, Nicolas Meyer
The combination of MEK inhibitor (cobimetinib, trametinib) and BRAF inhibitor (vemurafenib, dabrafenib) is now the first-line treatment in patients with BRAF V600-mutated metastatic melanoma. This association reduces cutaneous adverse events induced by BRAF inhibitors alone, including photosensitivity, hand-foot syndrome, hyperkeratosis, alopecia, skin papillomas, keratoacanthomas, and squamous-cell carcinomas. While panniculitis has exceptionally been reported with BRAF inhibitors, this rare side effect has never been described with the use of MEK inhibitors...
January 2017: Case Reports in Dermatology
https://www.readbyqxmd.com/read/28601879/outcomes-in-melanoma-patients-treated-with-braf-mek-directed-therapy-or-immune-checkpoint-inhibition-stratified-by-clinical-trial-versus-standard-of-care
#10
Chloe Goldman, Jeremy Tchack, Eric M Robinson, Sung Won Han, Una Moran, David Polsky, Russell S Berman, Richard L Shapiro, Patrick A Ott, Iman Osman, Hua Zhong, Anna C Pavlick, Melissa Ann Wilson
OBJECTIVES: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population...
June 10, 2017: Oncology
https://www.readbyqxmd.com/read/28599981/p90rsk-blockade-inhibits-dual-braf-and-mek-inhibitor-resistant-melanoma-by-targeting-protein-synthesis
#11
Nicholas Theodosakis, Goran Micevic, Casey G Langdon, Alessandra Ventura, Robert Means, David F Stern, Marcus W Bosenberg
Despite improvements in survival in metastatic melanoma with combined BRAF and MEK inhibitor treatment, the overwhelming majority of patients eventually acquire resistance to both agents. Consequently, new targets for therapy in resistant tumors are currently being evaluated. Previous studies have identified p90RSK family kinases as key factors for growth and proliferation, as well as protein synthesis via assembly of the m(7)-GTP cap-dependent translation complex. We sought to evaluate inhibitors of p90RSK family members: BI-D1870 and BRD7389, for their ability to inhibit both proliferation and protein synthesis in patient-derived melanoma cell lines with acquired resistance to combined treatment with the BRAF inhibitor vemurafenib and MEK inhibitor selumetinib...
June 6, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28599271/mtorc1-autophagy-regulated-mertk-in-mutant-brafv600-melanoma-with-acquired-resistance-to-braf-inhibition
#12
Gongda Xue, Reto Kohler, Fengyuan Tang, Debby Hynx, Yuhua Wang, Francesca Orso, Vincent Prêtre, Reto Ritschard, Petra Hirschmann, Peter Cron, Tim Roloff, Reinhard Dummer, Mario Mandalà, Sandrine Bichet, Christel Genoud, Alexandra G Meyer, Manuele G Muraro, Giulio C Spagnoli, Daniela Taverna, Curzio Rüegg, Taha Merghoub, Daniela Massi, Huifang Tang, Mitchell P Levesque, Stephan Dirnhofer, Alfred Zippelius, Brian A Hemmings, Andreas Wicki
BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28596940/histone-deacetylase-inhibitor-treatment-increases-the-expression-of-the-plasma-membrane-ca-2-pump-pmca4b-and-inhibits-the-migration-of-melanoma-cells-independent-of-erk
#13
Luca Hegedüs, Rita Padányi, Judit Molnár, Katalin Pászty, Karolina Varga, István Kenessey, Eszter Sárközy, Matthias Wolf, Michael Grusch, Zoltán Hegyi, László Homolya, Clemens Aigner, Tamás Garay, Balázs Hegedüs, József Tímár, Enikö Kállay, Ágnes Enyedi
Several new therapeutic options emerged recently to treat metastatic melanoma; however, the high frequency of intrinsic and acquired resistance among patients shows a need for new therapeutic options. Previously, we identified the plasma membrane Ca(2+) ATPase 4b (PMCA4b) as a metastasis suppressor in BRAF-mutant melanomas and found that mutant BRAF inhibition increased the expression of the pump, which then inhibited the migratory and metastatic capability of the cells. Earlier it was also demonstrated that histone deacetylase inhibitors (HDACis) upregulated PMCA4b expression in gastric, colon, and breast cancer cells...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28595656/ros-production-induced-by-braf-inhibitor-treatment-rewires-metabolic-processes-affecting-cell-growth-of-melanoma-cells
#14
Giulia Cesi, Geoffroy Walbrecq, Andreas Zimmer, Stephanie Kreis, Claude Haan
BACKGROUND: Most melanoma patients with BRAF(V600E) positive tumors respond well to a combination of BRAF kinase and MEK inhibitors. However, some patients are intrinsically resistant while the majority of patients eventually develop drug resistance to the treatment. For patients insufficiently responding to BRAF and MEK inhibitors, there is an ongoing need for new treatment targets. Cellular metabolism is such a promising new target line: mutant BRAF(V600E) has been shown to affect the metabolism...
June 8, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28594589/mek-inhibitors-in-oncology-a-patent-review-2015-present
#15
Debarshi Kar Mahapatra, Vivek Asati, Sanjay Kumar Bharti
The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways have been identified as promising therapeutic targets for cancer therapy. Over-activation of these pathways and their components including gene mutations has been considered as one of the major causes of melanoma. Mitogen-activated protein kinase (MEK) is a downstream kinase of RAS pathway found in two different forms MEK1/2. The MEK inhibitors in combination with other kinase/mutant gene inhibitors have shown promising results in patients with metastatic melanoma...
June 19, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28561662/systemic-therapy-options-for-patients-with-unresectable-melanoma
#16
Melinda Yushak, Paul Chapman, Caroline Robert, Ragini Kudchadkar
There has been a therapeutic revolution in the treatment of metastatic melanoma over the past decade. Patients presenting with inoperable disease have several therapeutic options, which can include both targeted and immune therapy. Immune checkpoint inhibitors have demonstrated an improvement in overall survival and led to some durable responses. However, toxicity, especially in combination regimens, can be severe. Adverse events should be anticipated, diagnosed as early as possible, monitored, and managed...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28556451/skin-cancers-in-organ-transplant-recipients
#17
Amit Mittal, Oscar R Colegio
Long-term utilization of immunosuppression in organ transplant recipients (OTRs) leads to decreased immune-mediated tumor surveillance and development of malignant tumors. A delicate balance needs to be maintained in the intensity of immunosuppression to keep the risk of malignancy low without jeopardizing life-saving graft function. OTRs are prone to developing skin cancers which exhibit unique epidemiologic, pathophysiologic and prognostic characteristics. In this review, we discuss the most commonly reported skin cancers in OTRs: squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Kaposi's sarcoma, Merkel cell carcinoma and malignant melanoma (MM)...
May 29, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28551858/cost-effectiveness-of-drug-treatments-for-advanced-melanoma-a-systematic-literature-review
#18
REVIEW
Darío Rubio-Rodríguez, Silvia De Diego Blanco, Maite Pérez, Carlos Rubio-Terrés
BACKGROUND: Until recently, advanced melanoma (unresectable and metastatic) has had a poor prognosis and has been treated with chemotherapy. The introduction of new treatments (BRAF and MEK inhibitors and immunotherapy) has improved overall survival and progression-free survival of some patients. OBJECTIVE: The objective of this study was to review the published evidence on the cost-effectiveness of pharmacological treatments for advanced melanoma. METHODS: A systematic literature search was conducted, without date or language restrictions, in PubMed, EMBASE, Scopus, the Cochrane Library, the UK National Institute for Health and Care Excellence databases and the Health Technology Assessment journal...
May 27, 2017: PharmacoEconomics
https://www.readbyqxmd.com/read/28551618/mek162-enhances-antitumor-activity-of-5-fluorouracil-and-trifluridine-in-kras-mutated-human-colorectal-cancer-cell-lines
#19
Jun Gong, Yuan Chen, Lixin Yang, Raju Pillai, Senji Shirasawa, Marwan Fakih
BACKGROUND: Preclinical evidence demonstrates that mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway inhibition increases sensitivity to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines and xenografts. Here, we aimed to investigate how CRC cell sensitivity to this combination is correlated to Kirsten rat sarcoma (KRAS) and proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) mutation, that are common in CRC and often lead to resistance to chemotherapy...
June 2017: Anticancer Research
https://www.readbyqxmd.com/read/28551613/erdheim-chester-disease-comprehensive-review-of-molecular-profiling-and-therapeutic-advances
#20
REVIEW
Faysal Haroun, Kristen Millado, Imad Tabbara
The revised 2016 World Health Organization classification introduced Erdheim-Chester disease (ECD) as a provisional entity within the histiocytic and dendritic cell neoplasms separate from the juvenile xanthogranuloma family based on distinct molecular features. However, evolving knowledge regarding the molecular and genetic aberrations in addition to common clinical features of ECD support the classification of ECD together with Langerhans cell histiocytosis (LCH). Accordingly, ECD can be thought of as an inflammatory myeloid clonal disorder based on the detection of various activating mutations along the mitogen activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) pathway with most notable variant being a valine to a glutamic acid substitution at amino acid 600 in the B-rapidly accelerated fibrosarcoma protein (BRAFV600E)...
June 2017: Anticancer Research
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