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PubMed Journals Articles About "Atezolizumab Plus Cobimetinib Vemurafenib BRAF Mutated Melanoma Patients" RSS

04:30 EST 25th February 2020 | BioPortfolio

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Showing "Atezolizumab plus cobimetinib vemurafenib BRAF mutated melanoma patients" PubMed Articles 1–25 of 36,000+

Validation of dabrafenib-trametinib prognostic groups in patients treated with vemurafenib and cobimetinib for advanced BRAF-mutated melanoma.

Prognostic groups defined by lactate dehydrogenase concentration and number of organ sites containing metastases have been reported for patients treated with dabrafenib and trametinib for advanced melanoma. We aimed to validate these prognostic groups for patients treated with vemurafenib and cobimetinib in the coBRIM and BRIM-3 clinical studies. Eight hundred nine patients were included, 240 treated with vemurafenib plus cobimetinib and 569 with vemurafenib. For patients treated with vemurafenib and cobime...


Effects of pharmacogenetic variants on vemurafenib-related toxicities in patients with melanoma.

The pharmacokinetics and pharmacodynamics of vemurafenib are characterized by a wide interpatient variability. Since multiple polymorphic enzymes and drug transporters are involved in vemurafenib pharmacokinetics, we studied associations of polymorphisms on vemurafenib-associated toxicities. Prospectively collected samples of 97 melanoma patients treated with vemurafenib alone (n = 62) or in combination with cobimetinib (n = 35) were genotyped for (3435C>T), (421C>A, 34G>A) and (, 15389C>T) polymorp...

A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein.

Melanoma is a highly aggressive tumor with a poor prognosis, and half of all melanoma patients harbor BRAF mutations. A BRAF inhibitor, vemurafenib (PLX4032), has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat advanced melanoma patients with BRAF mutation. However, the efficacy of vemurafenib is impeded by adaptive resistance in almost all patients. In this study, using a cell-based SELEX (systematic evolution of ligands by exponential enrichment) s...


Relationship between vemurafenib plasma concentrations and survival outcomes in patients with advanced melanoma.

Purpose To validate a plasma vemurafenib steady-state trough concentration (C,) threshold that predicts survival outcomes of patients with BrafV mutated melanoma.

HO-1 downregulation favors BRAF melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition.

Heme oxygenase 1 (HO-1) plays a pivotal role in preventing cell damage. Indeed, through the antioxidant, anti-apoptotic and anti-inflammatory properties of its metabolic products, it favors cell adaptation against different stressors. However, HO-1 induction has also been related to the gain of resistance to therapy in different types of cancers and its involvement in cancer immune-escape has been hypothesized. We have investigated the role of HO-1 expression in Vemurafenib-treated BRAF melanoma cells in mo...

Two cases of BRAF-mutated, bulbar conjunctival melanoma with review of the published literature.

We describe two cases of BRAF-mutated melanoma of the epithelioid cell type arisen from primary acquired melanosis with severe atypia on the right bulbar conjunctiva. Case 1 was a 71-year-old Japanese man. After adjuvant cryotherapy and enucleation of the right eyeball, therapy with vemurafenib was administered for a distant metastasis to a lumbar vertebra, accompanied by erythema multiforme and two keratinous tumors. The patient died due to metastases to the liver and multiple vertebrae despite therapy wit...

T-Type calcium channels as potential therapeutic targets in vemurafenib-resistant BRAF melanoma: TTCCs are therapy target in BRAF melanoma.

Melanoma is a malignant neoplasia that is highly resistant to chemotherapy and radiotherapy and is associated with poor prognosis in advanced stage. Targeting melanoma that harbors the common BRAF mutation with kinase inhibitors, such as vemurafenib, reduces tumor burden, but these tumors frequently acquire resistance to these drugs. We previously proposed that T-type calcium channel (TTCC) expression may serve as a biomarker for melanoma progression and prognosis, and we showed that TTCC blockers reduce mi...

Clinical significance of BRAF/NRAS concurrent mutations in a clinic-based metastatic melanoma cohort.

Innovative therapeutic strategies in metastatic melanoma depend on molecular features and the combination of BRAF and MEK inhibitors (BRAFi+MEKi) which has recently shown an improved clinical efficacy in BRAF metastatic melanoma patients, is now the standard of care. BRAF and NRAS activating mutations lead to the MAPK pathway deregulation and may coexist despite their earlier description as mutually exclusive . This event is probably related to the existence of several mutually-exclusive subclones correspon...

Effects of Glutathione Transferase-Targeting Nitrobenzoxadiazole Compounds in Relation to PD-L1 Status in Human Melanoma Cells.

PD-L1 is a membrane protein with inhibitory effects on immune responses, whose expression has been correlated with high aggressiveness and the propensity of melanoma to metastasize. The nitrobenzoxadiazole (NBD) NBDHEX and its analog MC3181 are endowed with strong antitumor activity towards melanoma and a significant ability to reduce its adhesion and invasiveness. Therefore, we investigated whether PD-L1 status could affect cell sensitivity to the cytotoxic effects of NBDs. We then evaluated the effects of...

Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II).

In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patt...

Mitogen-activated protein kinase dependency in BRAF/RAS wild type melanoma: a rationale for combination inhibitors.

Inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint molecules have dramatically improved the survival of patients with BRAF -mutant melanoma. For BRAF/RAS wild type (WT) melanoma patients, however, immune checkpoint inhibitors remain the only effective therapeutic option with 40% of patients responding to PD-1 inhibition. In the present study, a large panel of 10 BRAF -mutant and 13 BRAF/RAS WT melanoma cell lines was analyzed to examine MAPK dependency and explore...

Role of VEGFR-1 in melanoma acquired resistance to the BRAF inhibitor vemurafenib.

The vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor frequently expressed in melanoma. Its activation by VEGF-A or placental growth factor (PlGF) promotes tumour cell survival, migration and invasiveness. Moreover, VEGFR-1 stimulation contributes to pathological angiogenesis and induces recruitment of tumour-associated macrophages. Since melanoma acquired resistance to BRAF inhibitors (BRAFi) has been associated with activation of pro-angiogenic pathways, we have investi...

Induced sarcoid-like reactions in patients with metastatic melanoma treated with dabrafenib and trametinib: a monocentric retrospective study.

Combined BRAF and MEK inhibition is one of the first-line treatment strategies for patients with advanced BRAF-mutant melanoma. Sarcoid-like reactions (SLRs) have occasionally been described with melanoma systemic treatments such as immunotherapy or the BRAF inhibitor vemurafenib, but very few cases have been reported with dabrafenib and trametinib. Our aim was to better characterize SLR induced by this combination. We conducted a monocentric retrospective observational study among patients treated with dab...

TERT, BRAF, and NRAS mutational heterogeneity between paired primary and metastatic melanoma tumors.

Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequency of inter- and intra-tumoral heterogeneity is controversial. We examined mutational heterogeneity within individual melanoma patients using multi-platform analysis of commonly mutated driver and non-passenger genes. We analyzed paired primary and metastatic tumors from 60 patients, and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n=271 tumors). We used a combina...

Brafv600e Mutation As A Prognostic Factor In Cutaneous Melanoma Patients.

The prognostic significance of BRAF mutations in the natural course of melanoma is controversial. The aim of study was to assess the prognostic significance of BRAF V600E mutation in cutaneous melanoma patients. A total of 151 melanomas were included in the study. BRAF V600E mutation was detected using the Real Time PCR. BRAF V600E mutation rate was 51%. BRAF mutation rate was higher for young patients (61.4%) and upper limbs (63.2%), trunk (59.3%) and head&neck (59.2%) were the most frequently afflicted si...

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity.

BRAF V600E is a common oncogenic driver in a variety of primary brain tumors. Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma. Here, the authors report on the subst...

Combined ipilimumab and nivolumab first-line and after BRAF targeted therapy in advanced melanoma.

Combination ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of BRAF targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and surv...

Targeted Therapy in Advanced Melanoma With Rare Mutations.

BRAF/MEK inhibition is a standard of care for patients with V600E/K-mutated metastatic melanoma. For patients with less frequent mutations, however, efficacy data are limited.

Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques.

The identification of the V600E activating mutation in the protein kinase BRAF in around 50% of melanoma patients has driven the development of highly potent small inhibitors (BRAFi) of the mutated protein. To date, Dabrafenib and Vemurafenib, two specific BRAFi, have been clinically approved for the treatment of metastatic melanoma. Unfortunately, after the initial response, tumors become resistant and patients develop a progressive and lethal disease, making imperative the development of new therapeutic o...

Quantification of cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and its metabolite regorafenib M2 in human plasma by UPLC-MS/MS.

A sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of seven oral oncolytics (two PARP inhibitors, i.e. olaparib and niraparib, and five tyrosine kinase inhibitors (TKIs), i.e. cobimetinib, cabozantinib, dabrafenib, vemurafenib, and regorafenib plus its active metabolite regorafenib M2) in EDTA plasma was developed and validated. Stable isotope-labeled internal standards were used for each analyte. A simple pr...

Clinical implications of ALDH1A1 and ALDH1A3 mRNA expression in melanoma subtypes.

Aldehyde dehydrogenase (ALDH) activity is not only a valuable marker for cancer cells with stem-like features, but also plays a vital role in drug resistance and disease progression in many tumors including melanoma. However, the precise role of ALDH activity in patient prognosis remains unclear. In this study, using the Cancer Genome Atlas (TCGA) RNA-sequencing expression data, we analyzed gene expression of ALDH isozymes in melanoma tumors to define the expression patterns and the prognostic and predictiv...

Considering adjuvant therapy for stage II melanoma.

Melanoma is among the few cancers that demonstrate an increasing incidence over time. Simultaneously, this trend has been marked by an epidemiologic shift to earlier stage at diagnosis. Before 2011, treatment options were limited for patients with metastatic disease, and the median overall survival was less than 1 year. Since then, the field of melanoma therapeutics has undergone major changes. The use of anti-CTLA-4 and anti-PD1 immune checkpoint inhibitors and combination BRAF/MEK inhibitors for patients...

Intermittent Versus Continuous Dosing of MAPK Inhibitors in the Treatment of BRAF-Mutated Melanoma.

The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi ± MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a...

Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials.

Previous analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients.

Frequency of somatic mutations in head and neck melanoma: A single institution experience.

Cutaneous head and neck melanoma (HNM) is a separate subgroup of cutaneous melanoma that has a worse prognosis than other primary sites. The aim of this article is to examine the status of somatic mutations (BRAF, NRAS, and KIT) of primary lesion in head and neck regions in our institution experience. Mutational status was correlated to the clinicopathological features and the disease progression. We retrospectively analyzed 76 cases of primary HNM diagnosed from January 2005 to June 2017, from the database...


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