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.
2022-07-01 | GSE198290 | GEO
Project description:Cells were treated with either PBS (mock) or hydroxychloroquine (HCQ).
2022-02-17 | PXD029648 | Pride
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.
2022-01-07 | GSE193157 | GEO
Project description:Regorafenib increased M1/M2 ratio of BMDMs polarization and proliferation/activation of co-cultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream CREB-KLF4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells, whereas macrophage deletion negated regorafenib’s antitumor effects. Synergistic antitumor efficacy between low-dose regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.
2021-01-27 | GSE148948 | GEO
Project description:This study is an open label non randomized study of hydroxychloroquine (HCQ) with histone deacetylase (HDAC) inhibitor Vorinostat in patients with advanced solid tumors to determine the maximum tolerated dose (MTD) and to evaluate the safety and antitumor activity of this drug combination.
| 2081555 | ecrin-mdr-crc
Project description:We report the RNA sequencing data from the REPEAT study, in which patients with beyond first-line esophagogastric cancer were treated with regorafenib and paclitaxel. For the RNA sequencing, biopsies from metastatic lesions were obtained on baseline (n=21) and fifteen days following treatment initiation (n=13). PURPOSE: Regorafenib monotherapy, a multikinase-inhibitor of angiogenesis, tumor microenvironment, and oncogenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in advanced esophagogastric cancer (EGC) patients refractory to first-line treatment, and explore potential biomarkers. METHODS: Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on day 1-21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall- (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second/third line systemic treatment. Paclitaxel pharmacokinetics were assessed using D1 and D15 samples. We performed ELISA measurements of galectin-1, RNA sequencing and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. RESULTS: In the dose-escalation cohort (n=14), the MTD of regorafenib was 120 mg. Thirty-four patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ≥3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up 7.8 months). OS (p=0.08) and PFS (p=0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p<0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p<0.01). Enrichment of angiogenesis-related gene expression was observed in short-survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p=0.02) and PFS (p=0.02). CONCLUSION: Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response.
2022-03-11 | GSE198136 | GEO
Project description:Hydroxychloroquine inhibits trained immunity
| PRJNA670179 | ENA
Project description:Low-dose regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR antibody) but produced higher T cell activation and M1 macrophage polarization, Regorafenib increased M1/M2 ratio of BMDMs polarization and proliferation/activation of co-cultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream CREB-KLF4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells, whereas macrophage deletion negated regorafenib’s antitumor effects. Synergistic antitumor efficacy between low-dose regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.
2021-01-27 | GSE148947 | GEO