Phase I/II Trial of Regorafenib, Hydroxychloroquine, and Entinostat in Metastatic Colorectal Cancer
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ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2249147 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Purpose: To investigate the inhibition of inflammatoty cytokines of Hydroxychloroquine to phagocytic THP-1 cells. Methods: we established a cell model of hemophagocytosis by simulating THP-1 cells with CpG-c for 24h in vitro to produce macrophages, and then coculture the cells with human RBCs. RNA sequencing analysis of THP-1 cells were performed to find Gene changed with CpG-c stimulation and Hydroxychloroquine intervention. Results:CpG-c sitimulation significantly altered gene expression of THP-1 cells. Cytokine genes were upregulated, especially a significant increase in IL-6 level from scratch. HCQ significantly inhibited the expression of inflammatory cytokines and decreased IL-6 gene level to baseline. Conclusions:Hydroxychloroquine can inhibite cytokine genes, especially IL-6 Gene level of THP-1 cells caused by CpG-c sitimulation.
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Project description:Cells were treated with either PBS (mock) or hydroxychloroquine (HCQ).
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Project description:Several Human PDA Cell Lines (ASPC1, PANC1, KP4, HPAFII, PATU8988S, PK45H, S2013, CAPAN1, BXPC3, HPAC, SW1990, MIAPACA2) were cultured and treated with DMSO, Trametinib (TRAM), Hydroxychloroquine (HCQ) and the combination of them before being prepared for Single-Cell RNA Sequencing
2026-01-16 | GSE310584 | GEO
Project description:Hydroxychloroquine (HCQ) is an autophagy inhibitor that has been used for the treatment of many diseases, such as malaria, rheumatoid arthritis, systemic lupus erythematosus, cancer, and so on. Despite the therapeutic advances in these diseases, the underlying mechanisms have not been well determined and hinder the rational use of this drug in the future. Here, we explored the possible mechanisms and identified the potential binding targets of HCQ by performing quantitative proteomics and thermal proteome profiling on MIA PaCa-2 cells. This study revealed that HCQ may exert its functions by targeting or regulating the expression of some autophagy-related proteins, such as galectin-8 (LGALS8), mitogen-activated protein kinase 8 (MAPK8), Ribosyldihydronicotinamide dehydrogenase (NQO2), Transport protein Sec23A (SEC23A), and so on. Furthermore, HCQ may prevent the progression of pancreatic cancer by regulating the expression of Nesprin-2 (SYNE2), Protein-S-isoprenylcysteine O-methyltransferase (ICMT) and Cotranscriptional regulator FAM172A (FAM172A). Therefore, these findings not only identify potential binding targets for HCQ but also revealed the non-canonical mechanisms of HCQ that may contribute to pancreatic cancer treatment.
2022-10-13 | PXD034196 | Pride
Project description:Purpose: In order to explore the mechanism of hydroxychloroquine (HCQ) in treating vitiligo. We report the application of transcriptome profiling (RNA-seq) in human vitiligo melanocytes cell line PIG3V after HCQ treatment. Methods: The PIG3V cells were divided randomly in two groups: HCQ treatment (1 μg/mL, 24 hours) and the cells without treatment (only medium). RNA samples extracted from PIG3V cells were quantified by NanoDrop and Bioanalyzer. After 2 rounds of purification Poly A RNA was extracted then from total RNA by using Dynabeads Oligo. Small pieces of Poly A RNA were returned through Magnesium RNA Fragmentation Module under the condition of 94℃ for 5 minutes. Subsequently, SuperScript Reverse Transcriptase was used to reverse-transcribe the cleaved RNA pieces into cDNA. Then, U-labeled second-stranded DNAs was synthesized. After adding of A-base to each strand, preparing for indexed adapters, and heat-labile UDG enzyme treatment, PCR amplification was performed under (1) 95℃, 3 minutes; (2) 98℃, 15 seconds for 8 cycles; (3) 60℃, 15 seconds, 72℃, 5 minutes. Ultimately, RNA sequencing was performed according to protocol of Illumina Novaseq™ 6000 (LC-Bio Technology CO., Ltd., Hangzhou, China). After calculation, differential expressed genes were screened by fold change (FC)＞2 or FC＜0.5 and p value＜0.05. Results: Using an optimized data analysis workflow, we mapped about 30 million sequence reads per sample and identified 60612 genes and 229420 transcripts. Approximately 0.3% of the genes showed differential expression between the HCQ treated PIG3V cells and the cells without HCQ, with a fold change＞2 or＜0.5 , p value＜0.05. Conclusions: Our research showed the first detailed transcriptome analysis of human vitiligo melanocytes PIG3V, with or without HCQ treatment. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses and permit the dissection of complex biologic mechanisms of HCQ in treating vitiligo.
2021-11-13 | GSE188603 | GEO
Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.
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Project description:Cells were treated with either PBS (mock) or hydroxychloroquine (HCQ).
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Project description:Objectives: Natural Killer (NK) cell dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis, but its underlying mechanisms remain poorly understood. This study investigates immunometabolic alterations in NK cells from SLE patients and explores therapeutic strategies for their restoration. Methods: We characterized mitochondrial structure and function in NK cells from the peripheral blood of SLE patients and healthy controls using flow cytometry, electron microscopy, and proteomics. Key mitophagy-related gene expressions were quantified using qPCR. The therapeutic effects of hydroxychloroquine (HCQ) on mitochondrial recycling and NK cell function were assessed in vitro. Results: SLE NK cells were characterized by an accumulation of enlarged, hyperpolarized mitochondria with cristae disorganization, and reduced mitophagy. Impaired lysosomal acidification and mtDNA extrusion into the cytosol were also observed. Treatment with hydroxychloroquine restored lysosomal pH, mitochondrial recycling, and NK cell effector functions, including cytokine production and cytotoxicity. Conclusions: This study identifies mitochondrial recycling dysfunction as a driver of NK cell abnormalities in SLE and highlights the potential of HCQ to restore NK cell functionality. These findings provide new insights into the immunometabolic mechanisms underlying SLE and suggest avenues for targeted therapeutic interventions.
2026-01-14 | PXD059825 | Pride
Project description:We performed single-cell RNA sequencing (scRNA-seq) of lung cells from hydroxychloroquine (HCQ)-treated mice to examine HCQ-induced IFN-I response in the lung.
2026-01-10 | GSE311755 | GEO
Project description:We performed RNA sequencing (RNA-seq) of granulocyte-macrophage colony-stimulating factor (GM-CSF) cultured bone marrow cells (GM-BMCs) treated with hydroxychloroquine (HCQ) or cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) to compare the gene expression profiles between HCQ and cGAMP treatments in GM-BMCs.
2026-01-10 | GSE312134 | GEO