SWOG S1400D (NCT02965378), a Phase II Study of the Fibroblast Growth Factor Receptor Inhibitor AZD4547 in Previously Treated Patients With Fibroblast Growth Factor Pathway-Activated Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy).
S1400D is a biomarker-driven therapeutic substudy Lung-MAP evaluate fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with squamous cell FGF-activated pathway.
This is the first Phase II trials to evaluate AZD4547 as a targeted approach in previously treated patients with squamous cell NSCLC FGFR-altered and is the first demonstration of the successful execution and behavior of a national umbrella protocol in this disease setting.Eligible patients had tumoral FGFR change or mutations and have progressive disease after at least one line of platinum-based systemic therapy.
Patients received AZD4547 80 mg twice a day orally. The primary endpoint was the response by Response Evaluation Criteria in Solid Tumors version 1.1; Secondary endpoints included progression-free survival, overall survival, and duration of response (DOR) .Ninety-two patients assigned to S1400D, 43 were enrolled, and 27 patients were treated AZD4547 was evaluated. evaluable patients was predominantly white (n = 24, 89%), median age 66 years (range, 49-88 years old) and women (n = 7, 26%). FGFR changes include FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%).
Treatment with ADZ4547 tolerated; Grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of the 27 patient-evaluated response, one patient with FGFR3 S249C had an unconfirmed partial response with dor 1.5 months and 1 patient with FGFR1 amplification has confirmed partial response with a bang of 2.9 months (7%, 95% confidence interval [CI ]: 0% -17%). Median progression-free survival and overall survival for AZD4547-treated cohort of 2.7 months (95% CI: 1.4 to 4.5 months) and 7.5 months (95% CI: 3.7 to 9.3 months). AZD4547 has an acceptable safety profile but minimal activity in this group is dominated FGFR1 / FGFR3-reinforced. Evaluation of other targeted agents in Lung-MAP is underway.
the important role of fibroblast growth factor signaling pathways in Ewing sarcoma octamer binding transcription factor 4 -mediated cell proliferation and tumorigenesis.
certain bone and soft tissue (BST) tumors harbor chromosomal translocation [t (6; 22) (p21; q12)], which fuses Ewing’s sarcoma (EWS) gene at 22q12 with octamer binding transcription factor 4 (Oct-4) gene on the 6p21 , resulting chimeric EWS-Oct-4 protein that has the ability of high transactivation.
Although the abnormal activation of signaling pathways can lead to the development of human cancer, pathways that underlie this process in tumor BST humans remain poorly explored. Here, we investigate the functional significance of fibroblast growth factor (FGF) signaling in human tumor BST. To identify the gene (s) involved in the FGF signaling pathway and potentially regulated by EWS-Oct-4 (also called EWS-POU5F1) we did an analysis of RNA-Seq, electrophoretic mobility shift test, chromatin immunoprecipitation test, and test xenograft.
Treating the cells expressing GBS6 or ZHBTc4-EWS-Oct-4 with a small molecule FGF receptor (FGFR) inhibitor PD173074, NVPBGJ398, ponatinib, and dovitinib suppressed cell proliferation. Gene expression analysis revealed that, among the 22 FGF and four family members Fgfr, FGF-4 showed the highest upregulation (by 145-fold) in cells expressing EWS ZHBTc4-October-4. computer-aided analysis to identify sites EWS-October-4-binding allegedly at + 3017 / + 3024, shows that the EWS-October-4 Organize FGF-4 expression in human tumor BST.
Description: CRK, also known as p38, is a protein that in humans is encoded by the CRK gene. This gene is a member of an adapter protein family that binds to several tyrosine-phosphorylated proteins. It is mapped to 17p13.3. The protein participates in the Reelin signaling cascade downstream of DAB1. The product of this gene has several SH2 and SH3 domains (src-homology domains) and is involved in several signaling pathways, recruiting cytoplasmic proteins in the vicinity of tyrosine kinase through SH2-phosphotyrosine interaction. The N-terminal SH2 domain of Crk functions as a positive regulator of transformation whereas the C-terminal SH3 domain functions as a negative regulator of transformation. Two alternative transcripts encoding different isoforms with distinct biological activity have been described.
Description: This recombinant p38 antibody reacts to human p38 MAPK. It may also react to the rat and mouse protein, as predicted by immunogen homology.
Description: P38 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress related transcription and cell cycle regulation, as well as in genotoxic stress response.
Description: P38 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress related transcription and cell cycle regulation, as well as in genotoxic stress response.
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IHC-P, IF, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of T180
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IHC-P, IF, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of T180
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IHC-P, IF, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of T180
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IF, IHC-P, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of Y182
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IF, IHC-P, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of Y182
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IF, IHC-P, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of Y182
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IHC-P, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of T180/Y182
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IHC-P, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of T180/Y182
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IHC-P, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of T180/Y182
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IHC-P, IF, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of Y323
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IHC-P, IF, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of Y323
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat. This p38 antibody is for WB, IHC-P, IF, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human p38 around the non-phosphorylation site of Y323
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat, Chicken. This p38 antibody is for WB, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from the C-terminal region of human p38
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat, Chicken. This p38 antibody is for WB, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from the C-terminal region of human p38
Description: A polyclonal antibody for detection of p38 from Human, Mouse, Rat, Chicken. This p38 antibody is for WB, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from the C-terminal region of human p38
FGF-4 enhancer construction showed that EWS-October-4 transactivated reporter FGF-4 gene in vitro, and that overexpression of EWS-Oct-4 stimulates endogenous FGF-4 gene expression in vivo. \
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