Sorafenib With Irinotecan in Metastatic Colorectal Cancer (mCRC) and K-RAS Mutation
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2078948 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC consented to baseline biopsies for pre-specified biomarkers assessment and biomarker discovery. Sorafenib was given at 400 mg orally twice daily until tumor progression or unacceptable toxicity. Outcomes by pre-specified biomarkers were analyzed and a Sorafenib sensitivity signature developed using high-throughput gene expression profiles of NSCLC cell lines and baseline biopsies. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG performance status of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Overall, 8-week DCR was 58.2%. Patients with EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Sorafenib sensitivity signature developed in cell lines was associated with an improved outcome. Conclusion: Patients with wild-type EGFR, including those with K-RAS mutation, may benefit from sorafenib as opposed to patients with EGFR mutation. We identify a gene expression signature associated with an improved outcome in patients with wild-type EGFR treated with sorafenib. BATTLE-2 trial is ongoing to validate those results. ClinicalTrials.gov number, NCT00411671. Gene expression profiles were measured in 37 core biopsies from patients with refractory non-small cell lung cancer treated with sorafenib in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We report a Sorafenib sensitivity gene expression signature trained in vitro (separate GEO submission), and tested in baseline biopsies collected in the BATTLE trial.
2014-06-01 | E-GEOD-31428 | biostudies-arrayexpress
Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC consented to baseline biopsies for pre-specified biomarkers assessment and biomarker discovery. Sorafenib was given at 400 mg orally twice daily until tumor progression or unacceptable toxicity. Outcomes by pre-specified biomarkers were analyzed and a Sorafenib sensitivity signature developed using high-throughput gene expression profiles of NSCLC cell lines and baseline biopsies. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG performance status of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Overall, 8-week DCR was 58.2%. Patients with EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Sorafenib sensitivity signature developed in cell lines was associated with an improved outcome. Conclusion: Patients with wild-type EGFR, including those with K-RAS mutation, may benefit from sorafenib as opposed to patients with EGFR mutation. We identify a gene expression signature associated with an improved outcome in patients with wild-type EGFR treated with sorafenib. BATTLE-2 trial is ongoing to validate those results. ClinicalTrials.gov number, NCT00411671.
2014-06-01 | GSE31428 | GEO
Project description:Primary objectives: The primary objective of the study is to define an optimal cut-off for anti-EGFR treatment with panitumumab in combination with FOLFIRI of patients with low-frequency RAS mutation defined by digital Next Generation Sequencing (dNGS) using the Oncomine cfDNA pan-cancer panel assay (52 genes) on an Ion Torrent S5 Prime platform. This assay combined with unique molecular identifier (UMI) or molecular barcode technique allows the exact quantification of mutation frequencies.
Primary endpoints: As primary endpoint ORR according to RECIST 1.1 will be evaluated separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C).
| 2538373 | ecrin-mdr-crc
Project description:Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% acute myeloid leukemias (AML) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD+ AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow (BM) myeloblasts after 27 (range 21–84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54–287) days but the FLT3 and downstream effectors remained suppressed. Four pairs patients (before sorafenib treatment and after sorafenib relapse), total eight samples from four patients at the two time-points were subjected to microarray analysis. Gene expression profiling showed that leukemia cells which have become sorafenib resistant expressed a number of genes including ALDH1A1, JAK3 and MMP15, whose functions were unknown in AML. NOD/SCID mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain (TKD) mutations at D835 were identified in leukemia initiating cells (LIC) from samples before sorafenib treatment. LIC bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggested that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors. RNA from CD33+CD34+ myeloblasts at pre-sorafenib-treatment and post-sorafenib-relapse were collected and subjected to microarray analysis
2012-02-18 | E-GEOD-35907 | biostudies-arrayexpress
Project description:Sorafenib resistance up-regulated circRNA_104797 could be transmitted by exosomes and responsible for the spread of Sorafenib resistance among HCC cells. CircRNA_104797 was critical for Sorafenib resistance maintenance and silencing circRNA_104797 could substantially increase the efficacy of Sorafenib by inducing apoptosis. Mechanism dissection unveiled that circRNA_104797 could specifically sponge miR-103a-2-5p and miR-660-3p and act as a competing endogenous RNA (ceRNA), thus competitively activated wnt/β-catenin pathway and induced Sorafenib resistance. Meanwhile, LC-MS/MS also revealed that circRNA_104797 could specifically bind to translation related proteins, which might regulate downstream glycan biosynthesis and lipid metabolism, and finally induce Sorafenib resistance. In vivo experiments portrayed a promising clinical application by locally injection of in vivo-grade siRNA for circRNA_104797 by TACE or other manners, which could intensively enhance Sorafenib efficacy in HCC patients. The clinical application of in vivo-grade siRNA for circRNA_104797 in Sorafenib treated HCC patients might shed bright future for the management of advanced HCC.
2020-07-25 | GSE101850 | GEO
Project description:Gene expression profiles were collected from HEK-HT cells expressing H-Ras with Ras-activating (G12V), Raf-activating (G12V,T35S), RalGEF-activating (G12V,E37G), or PI3K-activating (G12V,Y40C) mutations. Keywords: Comparison of Ras pathway components. THX=control; 12V=G12V mutation; 35S=G12V,T35S mutation; 37G=G12V,E37G mutation; 40C=G12V,Y40C mutation. 5 replicates of each. Total of 25 samples.
2009-02-21 | E-GEOD-14934 | biostudies-arrayexpress
Project description:We used an expression profiling chip to detect the expression profile of PLC cells after they were treated with sorafenib and sorafenib probe
2018-12-12 | GSE123600 | GEO
Project description:The present hypothesis is that anti-EGFR agents are active in tumors with low-level RAS mutation when the majority of tumor cells is still sensitive. While response rate may be high and may reflect sensitivity to anti-EGFR agents, PFS is anticipated to be shorter than in RAS wild-type patients due to the faster development of resistance when sensitive cells are eradicated and when the RAS-mutant anti-EGFR resistant clones become predominant.
The characteristics of low-level RAS mutant tumors would be:
* Objective response rate (ORR) high (reflecting the sensitive clone)
* Progression-free survival (PFS) short (reflecting the more rapid outgrowth of RAS mutant clones)
| 2312021 | ecrin-mdr-crc
Project description:Our gene set analysis of MV4-11-R versus MV4-11 indicated decreased depolarization of mitochondria and mitochondrial membrane, mitochondrial dysfunction and anti-apoptosis as other top ranked molecular or cellular functions of differential gene sets. expression of most genes encoding glycolytic enzymes was up-regulated in MV4-11-R cells we revealed a metabolic alteration in sorafenib-resistant cell lines with mitochondrial respiration deficiency, leading to substantial decrease of mitochondria-derived ATP generation and a significant increase in glycolytic activity to maintain sufficient ATP production. Our study revealed a metabolic signature of sorafenib resistance and indicated that increase of glycolytic activity including upregulation of major glycolytic enzymes may be viewed as a marker for early detection of sorafenib resistance in AML patients with FLT3/ITD mutation and glycolytic inhibitors warrant further investigation as alternative therapeutic agents for sorafenib-resistant cells Sorafenib resistant cells MV411-R VS. parental MV4-11 cells. Biological replicates: 3 control replicates, 3 treated replicates.
2016-08-01 | E-GEOD-74666 | biostudies-arrayexpress
Project description:Ras proteins are GTPases that regulate a wide range of cellular processes. The activity of Ras is dependent on its nucleotide-binding status, which is modulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Previously, we demonstrated that mutation of lysine 104 to glutamine (K104Q) attenuates the transforming capacity of oncogenic K-Ras by interrupting GEF induced nucleotide exchange. To assess the effect of this mutation in vivo, we used CRISPR/Cas9 to generate mouse models carrying the K104Q point mutation in wild-type and conditional K- RasLSL-G12D alleles. Homozygous animals for K104Q were viable, fertile, and arose at Mendelian frequency, indicating that K104Q is not a complete loss of function mutation. Consistent with our previous findings from in vitro studies, however, the oncogenic activity of K-RasG12D was significantly attenuated by mutation at K104. These data demonstrate that lysine at position 104 is critical for the full oncogenic activity of mutant K-Ras and suggest that modification at K104, for example acetylation, may also regulate its activity. Using biochemical and structural analysis, we found that the G12D and K104Q mutations cooperate to suppress GEF-mediated nucleotide exchange, explaining the preferential effect of K104Q on oncogenic K-Ras. Furthermore, we found that K104 site forms allosteric network with three residues (M72, R73 and G75) on 2 helix at switch II. Intriguingly, point mutation at glutamine 75 to alanine (G75A) showed strong negative regulatory effect on K-RasG12D. Collectively, modulating these sites may provide a unique therapeutic approach in cancer expressing mutant K-Ras.
2023-06-01 | GSE233945 | GEO