Sorafenib Plus Capecitabine (SorCape) in Previously Treated Metastatic Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colon Cancer,Colorectal Neoplasms,Colorectal Cancer Metastatic
PROVIDER: 2115642 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Lessons learnedTreatment for patients with metastatic colorectal cancer (mCRC) typically involves multiple lines of therapy with eventual development of treatment resistance. In this single-arm, phase II study involving heavily pretreated patients, the combination of sorafenib and capecitabine yielded a clinically meaningful progression-free survival of 6.2 months with an acceptable toxicity profile. This oral doublet therapy is worthy of continued investigation for clinical use in patients with mCRC.BackgroundCapecitabine (Cape) is an oral prodrug of the antimetabolite 5-fluorouracil. Sorafenib (Sor) inhibits multiple signaling pathways involved in angiogenesis and tumor proliferation. SorCape has been previously studied in metastatic breast cancer.MethodsThis single-arm, phase II study was designed to evaluate the activity of SorCape in refractory metastatic colorectal cancer (mCRC). Patients received Sor (200 mg p.o. b.i.d. max daily) and Cape (1,000 mg/m2 p.o. b.i.d. on days 1-14) on a 21-day treatment cycle. Primary endpoint was progression-free survival (PFS) with preplanned comparison with historical controls.ResultsForty-two patients were treated for a median number of 3.5 cycles (range 1-39). Median PFS was 6.2 (95% confidence interval [CI], 4.3-7.9) months, and overall survival (OS) was 8.8 (95% CI, 4.3-12.2) months. One patient (2.4%) had partial response (PR), and 22 patients (52.4%) had stable disease (SD) for a clinical benefit rate of 54.8% (95% CI, 38.7%-70.2%). Hand-foot syndrome was the most common adverse event seen in 36 patients (85.7%) and was grade ≥ 3 in 16 patients (38.1%). One patient (2.4%) had a grade 4 sepsis, and one patient (2.4%) died while on treatment.ConclusionSorCape in this heavily pretreated population yielded a reasonable PFS with manageable but notable toxicity. The combination should be investigated further.
| S-EPMC8100547 | biostudies-literature
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:Sorafenib is associated with cardiac adverse effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish. A pigmentless zebrafish line expressing green fluorescent protein in the heart were treated with or without sorafenib. In vivo fluorescent cardiac imaging revealed that the ventricular dimension of the longitudinal axis in zebrafish treated with sorafenib was significantly lower than in those without sorafenib. Transcriptome analysis of zebrafish hearts revealed that expression of stanniocalcin1 (stc1) in zebrafish treated with sorafenib was significantly lower than that without sorafenib treatment. We were able to demonstrate that the ventricular dimension of the longitudinal axis in stc1 morphant was significantly smaller than that of control zebrafish and that forced expression of stc1 normalized the decrease in ventricular diameter in stc1 morphant and zebrafish treated with sorafenib. These data suggest that stc1 is the gene responsible for sorafenib-induced cardiotoxicity. Gene expression regulated by sorafenib in zebrafish at 4 dpf was measured. Four independent experiments were performed for each group.
2014-12-04 | E-GEOD-61155 | biostudies-arrayexpress
Project description:In our experiments with a xenograft model, mouse-IFN (mIFN) treatment was suggested to exaggerate the antitumor effects of sorafenib on hepatocellular carcinoma in vivo. We explored how mIFN enhances the in vivo antitumor effects of sorafenib.
2017-11-01 | GSE102863 | GEO
Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.
2016-06-16 | E-GEOD-73571 | biostudies-arrayexpress
Project description:PLC-PRF-5 cells treated with sorafenib, sorafenib probe or DMSO
| PRJNA509351 | ENA
Project description:Sorafenib is associated with cardiac adverse effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish. A pigmentless zebrafish line expressing green fluorescent protein in the heart were treated with or without sorafenib. In vivo fluorescent cardiac imaging revealed that the ventricular dimension of the longitudinal axis in zebrafish treated with sorafenib was significantly lower than in those without sorafenib. Transcriptome analysis of zebrafish hearts revealed that expression of stanniocalcin1 (stc1) in zebrafish treated with sorafenib was significantly lower than that without sorafenib treatment. We were able to demonstrate that the ventricular dimension of the longitudinal axis in stc1 morphant was significantly smaller than that of control zebrafish and that forced expression of stc1 normalized the decrease in ventricular diameter in stc1 morphant and zebrafish treated with sorafenib. These data suggest that stc1 is the gene responsible for sorafenib-induced cardiotoxicity.
2014-12-04 | GSE61155 | GEO
Project description:To profile determinants of sensitivity and resistance towards the multikinase inhibitor sorafenib in liver cancer (HCC), we generated HCCs with elevated MYC expression and activated Raf-MEK-ERK signaling. To trigger tumor development, we co-delivered transposable elements encoding for Myc and oncogenic NrasG12V via hydrodynamic injection into the hepatocytes of C57BL/6 wildtype mice. To characterize the response of Myc/NrasG12V HCCs towards sorafenib, we analyzed their transcriptomes after three weeks of sorafenib or carrier treatment.
2020-12-01 | GSE162322 | GEO
Project description:BACKGROUND & AIMS: Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). In early-stage HCC, survival benefits of resection/local ablation are compromised by high recurrence rates (70% at 5-years). In this setting, the phase-3 STORM-trial did not achieve its primary end-point of improving recurrence-free-survival (RFS) comparing sorafenib to placebo as adjuvant treatment. Herein we present results of the biomarker companion study BIOSTORM in which we define predictors of recurrence prevention with sorafenib and prognostic factors with B-level of evidence. METHODS: Tumor tissue from 188 patients randomized to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene-expression profiling, targeted exome sequencing (18 known onco-drivers), immunohistochemistry (pERK, pVEGFR2, Ki67), FISH (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time-to-recurrence equaled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS: BIOSTORM recapitulates clinical and pathological characteristics of STORM patients. None of the biomarkers tested that are known to be related to angiogenesis and proliferation, or previously proposed gene-signatures, or mutations predicted sorafenib benefit. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p-of-interaction=0.04). These sorafenib responders were significantly enriched in CD4+ T, B, and cytolytic Natural Killer cells, and showed absence of activated macrophages and other components of adaptive immunity. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSIONS: In BIOSTORM, hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene-signatures predicted sorafenib benefit. A newly generated multi-gene signature associated with improved RFS on sorafenib warrants further validation. KEYWORDS: sorafenib; tyrosine-kinase inhibitor; trial enrichment; stratification.
2018-08-21 | GSE109211 | GEO
Project description:Quantitative proteomics in DIA mode was used to analysis the proteomic profile of 24 weeks from the sorafenib treated and vehicle treated monkeys.
2022-08-30 | PXD018256 | Pride