Study of Modified FOLFOX6 Plus or Minus Sorafenib in Stage IV Metastatic Colorectal Carcinoma (mCRC) Subjects
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ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,The Patient Population Includes Patients With Stage Iv Metastatic Colorectal Cancer (mcrc), With Eastern Cooperative Oncology Group (ecog) Performance Status 0 Or 1. Patients Must Have Measurable Disease And Must Not Have Received Prior Systemic Anticancer Therapy For Mcrc.,Colorectal Cancer,Colorectal Cancer Metastatic,Colorectal Neoplasms
PROVIDER: 2069610 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Background & Aims: Existing drug therapies for hepatocellular carcinoma (HCC), including sorafenib, extend patient survival by only three months. We sought to identify novel druggable targets for use in combination with sorafenib to increase its efficacy. Methods: We implemented an in vivo genetic screening paradigm utilizing a library of 43 genes-of-interest expressed in the context of repopulation of the injured livers of Fumarylacetoacetate Hydrolase-deficient (Fah-/-) mice, which led to highly penetrant HCC. We treated mice with vehicle or sorafenib, then determined the genetic drivers of each tumor from the library. Liver X Receptor alpha (LXRalpha) emerged as a potential target. To examine LXRalpha agonism in combination with sorafenib treatment, we added varying concentrations of sorafenib and LXRalpha agonist drugs to HCC cell lines. To elucidate the mechanism of tumor death, we performed transcriptomic analysis. Results: Fah-/- mice injected with the screening library developed HCC tumor clones containing Myc cDNA plus various other cDNAs. Treatment with sorafenib resulted in sorafenib-resistant HCCs that were significantly depleted in Nr1h3 cDNA, encoding LXRalpha, suggesting that LXRalpha activation is incompatible with tumor growth in the presence of sorafenib treatment in vivo. Combination treatment using sorafenib and LXR agonist drugs in multiple HCC cell lines led to enhanced cell death as compared to monotherapy, due to reduced expression of cell cycle regulators and increased expression of genes associated with apoptosis. Combination therapy also enhanced cell death in a sorafenib-resistant primary human HCC cell line. Conclusions: We have completed a novel drug resistance screen in vivo, and identified that LXR agonism potentiates the efficacy of sorafenib in treating HCC.
2020-05-29 | GSE151412 | GEO
Project description:Osteosarcoma is a rare but aggressive bone neoplasm in humans, which is commonly treated with surgery, classical chemotherapy and radiation. Here, we studied the antimetastatic potential of 4 M-NM-<M of the multikinase inhibitor Sorafenib in a human osteosarcoma cell line using DNA microarray-based gene expression profiling. 3 untreated replicates of human osteosarcoma cells (ATCC CRL-1543M-bM-^DM-"), 3 replicates of human osteosarcoma cells (ATCC CRL-1543M-bM-^DM-") treated with 4 M-BM-5M Sorafenib
2013-12-13 | E-GEOD-53155 | biostudies-arrayexpress
Project description:Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the emergence of sorafenib resistance in HCC patients. The underlying mechanism of sorafenib resistance is unclear. Here, we report a circular RNA, cDCBLD2, which plays an important role in sorafenib resistance in HCC. We found that cDCBLD2 was upregulated in sorafenib-resistant (SR) HCC cells, and knocking down cDCBLD2 expression could significantly increase sorafenib-related cytotoxicity. Further evidence showed that cDCBLD2 can bind to microRNA (miR)-345-5p through a competing endogenous RNA mechanism, increase type IIA topoisomerase (TOP2A) mRNA stability through a miRNA sponge mechanism, and reduce the effects of sorafenib treatment on HCC by inhibiting apoptosis. Our findings also suggest that miR-345-5p can negatively regulate TOP2A levels by binding to the coding sequence region of its mRNA. Additionally, targeting cDCBLD2 by injecting a specific small interfering RNA (siRNA) could significantly overcome sorafenib resistance in a patient-derived xenograft (PDX) mouse model of HCC. Taken together, our study provides a proof-of-concept for a potential strategy to overcome sorafenib resistance in HCC patients by targeting cDCBLD2 or TOP2A.
2023-12-11 | GSE240109 | GEO
Project description:Sorafenib is currently the standard treatment for advanced hepatocellular carcinoma (HCC). Epigenetic alterations such as DNA methylation, play a decisive role in the development and progression of HCC. To our knowledge, there are no studies that have analyzed the global DNA methylation changes in HCC cells treated with sorafenib. Using MeDip-chip technologies we analyzed sorafenib effects on the methylome of human HCC cells. We found 1230 differentially methylated genes in HA22T/VGH cells treated with sorafenib compared to untreated cells. Gene ontology and pathway analysis found enriched several GO terms related to transcription factors and different pathways involved in tumorigenesis and cancer progression. Among the genes differentially methylated we found genes related to apoptosis (FOXO3, SMAD2, p21), angiogenesis (EPAS1) and invasion (MMP3, MMP7, RAC1, RHOC), genes belonged to pathways deregulated in HCC such as RAF/MEK/ERK (MAPK3, MAP2K2), JNK (MAPK8, MAP2K7), JAK-STAT (JAK1, STAT3, STAT5, CCND3), PI3K/AKT/mTOR (TSC2, PRKCZ) and NF-κB (IKBKG, MALT1, MAP3K14) and cancer-associated non-coding genes such as MALAT1, miR-149 and miR-675. We found a general trend where oncogenes were hypermethylated and tumor suppressor genes were hypomethylated after sorafenib treatment. Finally, we validated MeDip-chip results on several differentially methylated genes using COBRA and direct bisulfite sequencing and for these genes we evaluated the relationship between methylation level and mRNA expression.Our results suggest that in HCC cells sorafenib could affect the methylation level of genes associated to cancer-related processes and pathways related to sorafenib mechanism of action. These results identified novel sorafenib targets genes which could be targets in a new design of multi-target and combined therapies, and to better understand the emergence of resistance in HCC.
2017-06-30 | GSE72257 | 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:To identify deregulated lncRNAs responsible for sorafenib unresponsiveness,
2018-06-30 | GSE87121 | 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.
2016-06-16 | GSE73571 | GEO
Project description:Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients’ survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
2017-03-19 | GSE96793 | GEO
Project description:Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients’ survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
2017-03-19 | GSE96792 | GEO
Project description:Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients’ survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
2017-03-19 | GSE96795 | GEO