Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tolerability and Safety of Vemurafenib, Cetuximab Combined With Camrelizumab for BRAF V600E-mutated /MSS Metastatic Colorectal Cancer

ABSTRACT: BRAF mutation exists in about 10-12% of colorectal cancer, among which BRAF V600E mutation is the most common type, which is an important biomarker for predicting the prognosis and precise treatment efficacy of metastatic colorectal cancer (mCRC). The prognosis of metastatic colorectal cancer with BRAF V600E mutation is very poor, with OS of about 6-9 months. Previous studies have shown that single anti-BRAF inhibitor are ineffective, while multi-target inhibitions of Ras-Raf -MEK pathway is a possible effective strategy for BRAF V600E-mutant mCRC. Currently, the proven effective regimens include the VIC regimen (Vemurafenib + cetuximab + Irinotecan) and BEACON regimen (Encorafenib+ cetuximab +/- Binimetinib) from the SWOGS1406 study. Furthermore, BRAF inhibitor +MEK inhibitor combined with PD-1 monoclonal antibody has been shown to be an effective strategy in BRAF V600E-mutant malignant melanoma, which promote the study of the regimens for the treatment of BRAF V600E-mutant mCRC. Increasing basic and clinical studies have shown that cetuximab has ADCC effect, induces immunogenic cell death, promotes immune cell infiltration and other immunomodulatory effects, and has a synergistic effect with PD-1 monoclonal antibody in colorectal cancer. Based on those theories, we conducted the phase I study to explore the safety and preliminary efficacy of the regimen of Vemurafenib (BRAFi) plus cetuximab (EGFRi) combined with PD-1 monoclonal antibody in BRAF V600E-mutant /MSS type mCRC.

DISEASE(S): Vemurafenib (brafi) Plus Cetuximab (egfri) Combined With Pd-1 Monoclonal Antibody,Colorectal Neoplasms,Braf V600e-mutated /mss Metastatic Colorectal Cancer

PROVIDER: 2387736 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

ACCESS DATA

Json Xml

Similar Datasets

Gene expression of the A375 melanoma cell line treated with RAF inhibitors Vemurafenib and time-course with EGF stimulation during Vemurafenib RAF inhibitor treatment alone or with the MEK inhibitor Cobimetinib

Project description:We treated for 24 hours the BRAF-V600E melanoma cell line A375 with 7 doses of the RAF inhibitor Vemurafenib and, in a second experimental desing, we treated for 24 hours the BRAF-V600E melanoma cell line A375 with Vemurafenib (1 uM) alone or in combination with the MEK inhibitor Cobimetinib (1 uM) and subsequently stimulated with EGF in a time-course of 7 time points for up to 8 hours (0, 0.5, 1, 2, 3, 4, 8 hours).

2020-10-19 | GSE127988 | GEO

Braf inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia, and exert anti-leukemic activity

Project description:Hairy cell leukemia (HCL) shows unique clinico-pathological and biological features. HCL responds well to purine analogues but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-MEK-ERK pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (Vemurafenib; Dabrafenib) or MEK (Trametinib) inhibitors. Results were validated in vivo in samples from Vemurafenib-treated HCL patients within a phase-2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, TRAP and cyclin-D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by co-culture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL. Analysis of differential gene expression in primary leukemic cells purified from peripheral blood of 6 HCL patients (from A to F), treated with Vemurafenib 1000 nM, in comparison with vehicle-treated (DMSO) HCL cells, for 48 hours or/and 72 hours. 24 gene expression profiles were analysed.

2014-12-12 | E-GEOD-63790 | biostudies-arrayexpress

Braf inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia, and exert anti-leukemic activity

2014-12-12 | GSE63790 | GEO

Expression data from BRAFV600E A375 melanoma cells treated with vehicle or vemurafenib

2014-05-20 | GSE42872 | GEO

Ezrin inhibition overcomes acquired resistance to vemurafenib in BRAFV600E-mutated colon cancer and melanoma cells in vitro

Project description:In spite of the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach. Our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers.

2023-08-29 | PXD042499 | Pride

RNAseq changes in mouse wound with or without time course treatment by Vemurafenib

Project description:BRAF inhibitors are highly effective therapies for patients with BRAF V600 mutated metastatic melanoma. Patients who receive BRAF inhibitors develop a variety of hyper-proliferative skin conditions, whose pathogenic basis is the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyper-proliferative skin changes improve when a MEK inhibitor is co-administered, as a MEK inhibitor blocks paradoxical MAPK activation. We tested whether we could take advantage of the mechanistic understanding of the skin hyper-proliferative side effects of BRAF inhibitors to accelerate skin wound healing by inducing paradoxical MAPK activation. Here we show that the BRAF inhibitor vemurafenib accelerates human keratinocyte proliferation and migration by increasing ERK phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing models in mice accelerated cutaneous wound healing and improved the tensile strength of healing wounds through paradoxical MAPK activation; addition of a MEK inhibitor reversed the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor did not increase the incidence of cutaneous squamous cell carcinomas in mice even after the application of a carcinogen. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds. Full depth incisional wound mice tissues with/without Vemurafenib treatment were sent for RNAseq analysis on day 2, 6 and 14

2016-07-29 | E-GEOD-74558 | biostudies-arrayexpress

Polyamine and EIF5A hypusination downstream of c-Myc confers targeted therapy resistance in BRAF mutant melanoma

Project description:BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance greatly compromises their therapeutic efficacy. Here, we elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reverses vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Finally, inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro and in vivo in a xenograft model. With the polyamine biosynthesis signature correlated with poor prognosis in BRAF mutant melanoma patients, our findings reveal that the polyamine-hypusination-mitochondrial respiration pathway is an effective therapeutic target that can maximize the therapeutic efficacy of existing BRAF inhibitors.

2024-07-10 | GSE243344 | GEO

Transcription profiling of human cell lines in culture (n=12) and murine xenografts (n=2) were treated with the MEK inhibitor PD0325901 or vehicle alone as controlPaired MEK inhibited and control

Project description:This study used microarray expression analysis to identify global changes in transcript alteration in response to MEK inhibition. Genes under ERK control were identified in a panel of V600E BRAF and RTK-activated tumor cells and xenografts, using short-term inhibition of ERK activity using the MEK inhibitor PD0325901 (Pfizer). Experiment Overall Design: Cell lines growing in culture (n=12) and murine xenografts (n=2) were treated with the MEK inhibitor PD0325901 or vehicle alone as control. Paired analysis of MEK inhibited to control samples was performed for two groups of tumor cells, V600E BRAF and RTK.

2009-02-21 | E-GEOD-10087 | biostudies-arrayexpress

Expression data from BRAFV600E A375 melanoma cells treated with vehicle or vemurafenib

Project description:Vemurafenib is a BRAF inhibitor with specificity for the most common BRAF mutant encountered in melanomas (BRAFV600E). Vemurafenib suppresses the proliferation of BRAF mutant human melanoma cells by suppressing downstream activation of the MEK/ERK mitogen activated protein kinases. We used microarrays to examine the transcriptional response of a vemurafenib-sensitive BRAFV600E human melanoma cell line (A375) to vemurafenib in order to further delineate the mechanisms by which BRAFV600E drives cell proliferation and energy metabolism in human melanoma. BRAFV600E A375 human melanoma cells were treated with vehicle (0.1% DMSO) or 10 uM vemurafenib for 24 h after which total RNA was extracted. Cells were prepared and RNA was extracted in 3 separate batches (three different cell stocks on three separate days) providing three independent replicates (n=3). Paired replicates (prepared from the same stock of cells on the same day) are denoted by A, B and C.

2014-05-20 | E-GEOD-42872 | biostudies-arrayexpress

The Efficacy of HLX208 (BRAF V600E Inhibitor) With Cetuximab for Metastatic Colorectal Cancer (mCRC) With BRAF V600E Mutation After First-line Treatment

Project description:An open, multicenter phase II clinical study to evaluate safety and efficacy of HLX208 (BRAF V600E inhibitor) combined with cetuximab for metastatic colorectal cancer (mCRC) with BRAF V600E Mutation after first-line treatment

| 2385031 | ecrin-mdr-crc

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data