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Binimetinib

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https://www.readbyqxmd.com/read/29767411/mek1-2-inhibition-by-binimetinib-is-effective-as-a-single-agent-and-potentiates-the-actions-of-venetoclax-and-abt-737-under-conditions-that-mimic-the-chronic-lymphocytic-leukaemia-cll-tumour-microenvironment
#1
Kyle Crassini, Yandong Shen, William S Stevenson, Richard Christopherson, Chris Ward, Stephen P Mulligan, O Giles Best
The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA)...
May 16, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29765547/signature-program-a-platform-of-basket-trials
#2
Eric D Slosberg, Barinder P Kang, Julio Peguero, Matthew Taylor, Todd M Bauer, Donald A Berry, Fadi Braiteh, Alexander Spira, Funda Meric-Bernstam, Steven Stein, Sarina A Piha-Paul, August Salvado
Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29653142/characterization-of-a-conjunctival-melanoma-cell-line-cm-as16-newly-established-from-a-metastatic-han-chinese-patient
#3
Yongyun Li, Qingfeng Shang, Peng Li, Jinfeng Cao, Liqi Zhu, Martine J Jager, Xianqun Fan, Shengfang Ge, Renbing Jia
Conjunctival melanoma (CM) is associated with metastases formation, can be fatal, and occurs in all different races. While cell lines are essential for experimental research, all available CM cell lines are derived from Caucasian patients. Furthermore, they are not derived from metastases. We aimed to establish a new CM cell line from a parotid metastasis in a Han Chinese patient and to depict its characteristics. The novel cell line, CM-AS16, was obtained from a surgical parotid sample and determined as a unique one with short tandem repeat (STR) analysis...
April 10, 2018: Experimental Eye Research
https://www.readbyqxmd.com/read/29573941/encorafenib-plus-binimetinib-versus-vemurafenib-or-encorafenib-in-patients-with-braf-mutant-melanoma-columbus-a-multicentre-open-label-randomised-phase-3-trial
#4
Reinhard Dummer, Paolo A Ascierto, Helen J Gogas, Ana Arance, Mario Mandala, Gabriella Liszkay, Claus Garbe, Dirk Schadendorf, Ivana Krajsova, Ralf Gutzmer, Vanna Chiarion-Sileni, Caroline Dutriaux, Jan Willem B de Groot, Naoya Yamazaki, Carmen Loquai, Laure A Moutouh-de Parseval, Michael D Pickard, Victor Sandor, Caroline Robert, Keith T Flaherty
BACKGROUND: Combined BRAF-MEK inhibitor therapy is the standard of care for BRAFV600 -mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600 -mutant melanoma. METHODS: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy...
March 21, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29356698/development-of-encorafenib-for-braf-mutated-advanced-melanoma
#5
Peter Koelblinger, Olaf Thuerigen, Reinhard Dummer
PURPOSE OF REVIEW: To describe the pharmacological properties, preclinical and clinical data of the novel V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-inhibitor encorafenib (LGX818) and to compare these with established BRAF-inhibitors in the treatment of locally advanced or metastatic melanoma. RECENT FINDINGS: Encorafenib has shown improved efficacy in the treatment of metastatic melanoma in comparison with vemurafenib. Combination with the MEK inhibitor (MEKi) binimetinib allows for higher dose intensities of encorafenib further improving response rates (RRs)...
March 2018: Current Opinion in Oncology
https://www.readbyqxmd.com/read/29245078/analysis-of-nras-gain-in-657-patients-with-melanoma-and-evaluation-of-its-sensitivity-to-a-mek-inhibitor
#6
Junya Yan, Xiaowen Wu, Jiayi Yu, Huan Yu, Tianxiao Xu, Kevin M Brown, Xue Bai, Jie Dai, Meng Ma, Huan Tang, Lu Si, Zhihong Chi, Xinan Sheng, Chuanliang Cui, Yan Kong, Jun Guo
BACKGROUND: Neuroblastoma rat-sarcoma (NRAS) mutations have been described in Chinese patients with melanoma. However, the status and the clinical significance of NRAS gain have not been investigated on a large scale. METHODS: A total of 657 melanoma samples were included in the study. NRAS copy number was examined using the QuantiGene Plex DNA assay. The sensitivities of cell lines and patient-derived xenograft (PDX) models containing NRAS gain to a MAP/ERK kinase (MEK) inhibitor (binimetinib) were also evaluated...
January 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#7
REVIEW
Chul Kim, Giuseppe Giaccone
The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC. Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents...
January 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29108355/a-phase-i-clinical-trial-of-binimetinib-in-combination-with-folfox-in-patients-with-advanced-metastatic-colorectal-cancer-who-failed-prior-standard-therapy
#8
May Cho, Jun Gong, Paul Frankel, Timothy W Synold, Dean Lim, Vincent Chung, Joseph Chao, Daneng Li, Yuan Chen, Stephen Sentovich, Kurt Melstrom, Gagandeep Singh, Eloise Luevanos, Marwan Fakih
Background: This was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX. Materials and Methods: Patients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29040252/in-the-pipeline-encorafenib-and-binimetinib-in-braf-mutated-melanoma
#9
Keith Flaherty
No abstract text is available yet for this article.
October 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28923937/direct-engagement-of-the-pi3k-pathway-by-mutant-kit-dominates-oncogenic-signaling-in-gastrointestinal-stromal-tumor
#10
Benedikt Bosbach, Ferdinand Rossi, Yasemin Yozgat, Jennifer Loo, Jennifer Q Zhang, Georgina Berrozpe, Katherine Warpinski, Imke Ehlers, Darren Veach, Andrew Kwok, Katia Manova, Cristina R Antonescu, Ronald P DeMatteo, Peter Besmer
Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic Kit V558Δ mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant Kit V558Δ/+ mice, double-mutant Kit V558Δ;Y567F/Y567F knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth...
October 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28921565/the-impact-of-p-glycoprotein-and-breast-cancer-resistance-protein-on-the-brain-pharmacokinetics-and-pharmacodynamics-of-a-panel-of-mek-inhibitors
#11
Mark C de Gooijer, Ping Zhang, Ruud Weijer, Levi C M Buil, Jos H Beijnen, Olaf van Tellingen
Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain...
January 15, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28919996/mek-inhibition-and-immune-responses-in-advanced-melanoma
#12
REVIEW
Reinhard Dummer, Egle Ramelyte, Sabrina Schindler, Olaf Thürigen, Mitchell P Levesque, Peter Koelblinger
phase II and III clinical trials demonstrated modest anti- tumor activity of Binimetinib (MEK162) - a potent allosteric inhibitor of MEK1 and MEK2- in patients with advanced NRAS mutant melanoma. The analysis of the NEMO study in NRAS mutated melanoma, has shown that pre-treatment with immunotherapy improved the outcome of binimetinib therapy. We discuss this finding in the context of in vitro and in vivo effects of MEK inhibition on immuno-critical pathways and interactions.
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28851243/binimetinib-for-the-treatment-of-nras-mutant-melanoma
#13
REVIEW
Paola Queirolo, Francesco Spagnolo
Activating NRAS mutations occur in approximately 15-20% of melanomas and are the second most common oncogenic driver mutation in this disease, after BRAF mutations. There is an unmet medical need for new targeted therapy opportunities in metastatic patients whose tumors harbor an NRAS mutation. Binimetinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, has shown clinical activity in this group of patients. Areas covered: The purpose of this paper was to review the safety, activity and efficacy of the MEK inhibitor binimetinib for the treatment of NRAS-mutant melanoma, as well as to discuss future therapeutic perspectives such as multiple pathways, targeted therapy, and combinations with immunotherapy...
November 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28746914/a-phase-i-clinical-trial-of-binimetinib-in-combination-with-folfox-in-patients-with-advanced-metastatic-colorectal-cancer-who-failed-prior-standard-therapy
#14
May Cho, Jun Gong, Paul Frankel, Timothy W Synold, Dean Lim, Vincent Chung, Joseph Chao, Daneng Li, Yuan Chen, Stephen Sentovich, Kurt Melstrom, Gagandeep Singh, Eloise Luevanos, Marwan Fakih
BACKGROUND: This was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX. MATERIALS AND METHODS: Patients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28724666/braf-inhibitors-amplify-the-proapoptotic-activity-of-mek-inhibitors-by-inducing-er-stress-in-nras-mutant-melanoma
#15
Heike Niessner, Tobias Sinnberg, Corinna Kosnopfel, Keiran S M Smalley, Daniela Beck, Christian Praetorius, Marion Mai, Stefan Beissert, Dagmar Kulms, Martin Schaller, Claus Garbe, Keith T Flaherty, Dana Westphal, Ines Wanke, Friedegund Meier
Purpose: NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its proapoptotic activity in BRAF-mutant melanoma...
October 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28711086/the-new-paradigm-of-systemic-therapies-for-metastatic-melanoma
#16
REVIEW
Virginia O Volpe, Daniel M Klufas, Upendra Hegde, Jane M Grant-Kels
New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.
August 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28640105/glomerulonephritis-and-granulomatous-vasculitis-in-kidney-as-a-complication-of-the-use-of-braf-and-mek-inhibitors-in-the-treatment-of-metastatic-melanoma-a-case-report
#17
Mehdi Maanaoui, Camille Saint-Jacques, Viviane Gnemmi, Marie Frimat, Arnaud Lionet, Marc Hazzan, Christian Noël, François Provot
RATIONALE: BRAF and MEK inhibitors have significantly improved the prognosis of metastatic melanoma, by inhibiting both the mitogen-activated protein kinase (MAP-kinase) pathway. They are associated with infrequent adverse kidney events. Most of these are related to the use of BRAF inhibitors and involve interstitial nephritis with acute tubular necrosis. PATIENT CONCERNS: We report a unique case of glomerulonephritis with renal granulomatous vasculitis in a patient diagnosed with metastatic melanoma treated with BRAF and MEK inhibitors...
June 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28587477/a-review-of-binimetinib-for-the-treatment-of-mutant-cutaneous-melanoma
#18
Peter Koelblinger, Joelle Dornbierer, Reinhard Dummer
Although significant progress has been made in the treatment of unresectable or metastatic melanoma, at least half of all advanced melanoma patients eventually progress and pass away due to their disease. In particular, patients with NRAS-mutated melanoma still face limited therapeutic options, with immunotherapy being the current treatment type of choice. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. The results of a recent Phase III trial rendered binimetinib the first targeted therapy agent to significantly improve progression-free survival in NRAS-mutated melanoma...
August 2017: Future Oncology
https://www.readbyqxmd.com/read/28537004/mek-inhibitors-in-the-treatment-of-metastatic-melanoma-and-solid-tumors
#19
REVIEW
Antonio M Grimaldi, Ester Simeone, Lucia Festino, Vito Vanella, Martina Strudel, Paolo A Ascierto
The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines...
December 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28513992/immunoregulatory-protein-b7-h3-promotes-growth-and-decreases-sensitivity-to-therapy-in-metastatic-melanoma-cells
#20
Karine Flem-Karlsen, Christina Tekle, Yvonne Andersson, Kjersti Flatmark, Øystein Fodstad, Caroline E Nunes-Xavier
B7-H3 (CD276) belongs to the B7 family of immunoregulatory proteins and has been implicated in cancer progression and metastasis. In this study, we found that metastatic melanoma cells with knockdown expression of B7-H3 showed modest decrease in proliferation and glycolytic capacity and were more sensitive to dacarbazine (DTIC) chemotherapy and small-molecule inhibitors targeting MAP kinase (MAPK) and AKT/mTOR pathways: vemurafenib (PLX4032; BRAF inhibitor), binimetinib (MEK-162; MEK inhibitor), everolimus (RAD001; mTOR inhibitor), and triciribidine (API-2; AKT inhibitor)...
September 2017: Pigment Cell & Melanoma Research
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