Combination therapies of porcupine inhibition with ruxolitinib, ibrutinib or belumosudil in murine sclerodermatous GvHD
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ABSTRACT:
PROVIDER: PRJNA1197368 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31694742_1.fastq.gz | Fastqsanger.gz | |||
| SRR31694742_2.fastq.gz | Fastqsanger.gz | |||
| SRR31694744_1.fastq.gz | Fastqsanger.gz | |||
| SRR31694744_2.fastq.gz | Fastqsanger.gz |
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Project description:Chronic graft-versus-host disease (cGvHD) is a frequent complication of allogeneic hematopoietic stem cell transplantation (alloSCT) and is associated with high morbidity and mortality. First drugs have been recently approved for the treatment of cGvHD, but the response rates are suboptimal and treatment discontinuation due to side effects remains frequent. Here, we evaluated the efficacy and safety profile of porcupine inhibition by Wnt-C59 in monotherapy or in combination with ruxolitinib, ibrutinib or belumosudil in experimental sclerodermatous GvHD (sclGvHD). Treatment was well tolerated in all groups with improvements in clinical and histological features. Of these, ruxolitinib in monotherapy, and the combination therapies demonstrated the highest efficacy. The combination therapies of Wnt-C59 with ibrutinib or belumosudil showed additive antifibrotic effects in skin and lungs compared to the respective monotherapies. Our study may have direct translational relevance, since: 1) core signaling pathways targeted by these drugs were enriched in both human and murine sclGvHD, and 2) ruxolitinib, ibrutinib and belumosudil are already approved for the treatment of cGvHD, and porcupine inhibitors are in clinical trials for other fibrotic diseases. Thus, simultaneous targeting of different pathogenetically relevant pathways might be a safe and effective therapeutic approach in sclGvHD.
2025-04-02 | GSE284107 | GEO
Project description:Aplastic anaemia (AA) is a disease that shows complex pathogenesis involving multiple immune factors. While immunosuppressive therapies such as cyclosporine can effectively control AA, they may be ineffective in certain patients or those with relapse. Therefore, new treatments are needed. Among the targets for these treatments, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway regulates inflammatory cytokines and immune activation. Ruxolitinib, a JAK1/2 inhibitor, reduces T-cell activation and the associated inflammatory response and improves AA disease status in mice. However, its mechanism of action is unclear; thus, further research is needed before its clinical use. We previously showed increased pyroptosis in patients with severe AA (SAA) and that macrophage pyroptosis is an important factor in immune activation. The current study investigated the interaction of ruxolitinib with macrophages and whether the drug could treat SAA by improving pyroptosis levels. We induced differentiation of the THP-1 human monocyte cell line into macrophages in vitro and then induced pyroptosis. After constructing a macrophage pyroptosis model, treatment with different concentrations of ruxolitinib was administered. The results showed that ruxolitinib reduced the levels of pyroptosis and inflammatory-related factors. A mouse model of SAA was validated. In conclusion, ruxolitinib may treatment affects SAA by reducing the level of macrophage pyroptosis.
2025-03-18 | GSE291850 | GEO
Project description:Background: Preclinical work has demonstrated that ibrutinib inhibits the generation, migration and immunosuppressive function of myeloid-derived suppressor cells (MDSC). A pilot study tested the combination of ibrutinib and nivolumab in patients with metastatic solid tumors. Methods: Sixteen patients with metastatic solid malignancies were treated with ibrutinib (420 mg) daily and nivolumab (240 mg) IV on days 1 and 15 of 28 day cycles. Ibrutinib dosing started 7 days before cycle 1 of nivolumab and was given until cycle 1, day 8 of nivolumab. The effect of ibrutinib alone and in combination with nivolumab on circulating MDSC and immune subsets and cytokine/chemokine levels were measured. Single-cell RNA and TCR sequencing was also performed. Results: The most common treatment-related AEs were fatigue (31%) and anorexia (31%). Five patients had a clinical response (4 partial, 1 complete). Four patients had stable disease at 3 months. Median progression-free survival was 3.5 months and median overall survival 10.8 months. MDSC levels increased following 7 days of single-agent ibrutinib compared to baseline (21.91% vs. 27.67%). There was increased T cell proliferation in response (33.9% vs. 40.06%, p<0.01) to the combination regimen. Plasma levels of CCL2, CCL3, CCL4, CCL13, IL- 8, and VEGF-α decreased with ibrutinib treatment. Ibrutinib treatment altered the transcriptional state of the myeloid cell compartment and led to increased cancer-associated TCR clonotypes. Conclusion: The combination of ibrutinib and nivolumab was well tolerated and ibrutinib significantly impacted MDSC and T cell function in patients with solid metastatic tumors.
2022-06-24 | GSE178882 | GEO
Project description:We established two representative ABC DLBCL cell lines (TMD8 and OCI-Ly10) with ibrutinib resistance by gradually increasing the concentration of ibrutinib during passage in culture. RNA-seq analysis demonstrated that the BCR pathway gene signature is enriched in resistant cell lines when compared to parental cells. The most upregulated gene is EGR1, a transcription factor that activates multiple oncogenic pathways including MYC and E2F. Elevated EGR1 expression is also observed in ibrutinib-resistant primary mantle cell lymphoma cells when treated with ibrutinib. Using multiple metabolic and genetic approaches, we discovered that overexpression of EGR1 causes metabolic reprogramming to oxidative phosphorylation (OXPHOS) and ibrutinib resistance. Mechanistically, EGR1 mediates metabolic reprogramming through transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation accelerates intracellular ATP production via the mitochondrial tricarboxylic acid (TCA) cycle, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in patient-derived xenograft mouse models.
2023-12-06 | GSE223150 | GEO
Project description:Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in developed countries. Ibrutinib (PCI-32765), a specific and irreversible inhibitor of Bruton's Tyrosine Kinase (BTK) represents a major step forward in the treatment of CLL. We have undertaken a detailed analysis of the changes happening to the chromatin structure in CLL cells from patients continuously receiving oral doses of ibrutinib. ChIP-seq has been performed for H3K4me3, H3K27ac, H3K27me3 and EZH2 up to 56 days following the beginning of the treatment. We observed that Ibrutinib-dependent lymphocytosis correlates with a global and transient recruitment of EZH2 to active cis-regulatory elements and increased H3K27me3.
2019-06-01 | E-MTAB-6410 | biostudies-arrayexpress
Project description:Myelofibrosis (MF) is a deadly blood neoplasia that presents the worst prognosis among myeloproliferative neoplasms (MPN). Expression of CDK6 is significantly elevated in MPN/MF hematopoietic progenitor cells. In this study, we investigated the efficacy of CDK4/6 inhibitor Palbociclib alone or in combination with Ruxolitinib in Jak2V617F and MPLW515L murine models of MF. Treatment of Palbociclib alone significantly reduced leukocytosis, splenomegaly and inhibited bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of Palbociclib and Ruxolitinib resulted in normalization of peripheral blood leukocyte counts, marked reduction of spleen size and abrogation of bone marrow fibrosis in murine models of MF. Mechanistically, we show that Palbociclib treatment or depletion of CDK6 inhibits Aurora kinase, NF-κB and TGF-β signaling pathways in Jak2V617F mutant hematopoietic cells. Overall, our data suggest that Palbociclib in combination with Ruxolitinib may have therapeutic potential for treatment of MF.
2021-11-05 | GSE173814 | GEO
Project description:By using a unique functional protein microarray platform, we found that the FDA approved drug ibrutinib can inhibits ERBB4 activity in the same nM range as its canonical target, BTK. Cell-based assays revealed that ibrutinib treatment inhibited cell growth in some ERBB4 expressing cancer cells whereas no response was observed in other cells. Therefore, to identify global gene expression differences between ibrutinib responsive and non-responsive cancer cells, we performed RNA-Seq, and identified a signature featuring the WNT pathway that predicts growth responsiveness to ibrutinib in ERBB4 expressing cancers.
2018-02-07 | GSE102744 | GEO
Project description:CTL exhaustion is driven by chronic antigen stimulation and is characterized by specific molecular, phenotypic and functional changes. Reversing CTLs exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. However, the therapeutic effects of ICB varies among patients and cancer types. Ibrutinib, a potent BTK inhibitor, is reported that it improved T cell function in ibrutinib long-term treated chronic lymphocytic leukemia patients. However, the mechanism remains unclear. We hypothesized ibrutinib can directly act on CD8+ T cells and reinvigorates exhausted CTLs. To test this, we generated in vitro exhausted OT-I cells as previously described (Zhao M et al PLoS Pathog. 16(6): e1008555) by repeatedly stimulating cells with SIINFEKL peptide. We tested the effect of ibrutinib on inhibitory receptor, exhaustion-related transcription factor expression and cytokine (IFNγ, TNFα and IL-2) production. We found that ibrutinib decreased the expression of multiple inhibitory receptors on in vitro exhausted CTL while the critical transcription factor, Tox was downregulated. The cytokine production of exhausted cells was partially improved after ibrutinib treatment. Importantly, using btk deficient mice we found the effect of ibrutinib was independent of BTK expression. To conclude, these findings suggest that ibrutinib reduces CTL exhaustion. Our study provides evidence for ibrutinib’s synergistic use with cancer immunotherapy.
2023-09-06 | GSE220433 | GEO
Project description:Background and methods: Ruxolitinib (RUX), a Jak1/2 inhibitor, has been reported to attenuate murine bone marrow failure recently. Its potential toxocicty of anemia and thrombocytopenia in human remains a concern. We tested the toxicity of ruxolitinib on hematopoiesis in normal mice by feeding the mice with RUX chow for 3 months. Bone marrow Lin-CD117+ cells were sorted from treated or untreated mice. RNA-Seq and analysis was performed using SMART-Seq mRNA LP Kit (Takara) and the Illumina Novaseq6000, according to the Institute's protocols. Results: Ruxolitinib reduced RBC and lymphocytes, but did not affect NEU and PLT in normal mice. RNA sequencing demonstrated that HSPCs from RUX-treated and untreated mice had overlapped transcriptome distribution in multiple dimentional scalling plot, indicating overall similarity at molecular level. Conclusion: Our results demonstrate that ruxolitinib has minimal toxicity on hematopoiesis in normal mice.
2024-05-08 | GSE240866 | GEO
Project description:BACKGROUND - IL-6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem cell transplantation (alloSCT) and is an attractive therapeutic target. METHODS - A registered phase I/II study (ACTRN12612000726853) of IL-6 receptor (IL-6R) neutralizing antibody administration on day -1 to patients receiving full or reduced-intensity conditioning (RIC) and alloSCT from HLA-matched sibling or unrelated donors with standard cyclosporin and methotrexate GVHD prophylaxis. The primary endpoint was incidence of grade II-IV acute GVHD. Outcomes were compared to a non-randomized but contemporaneous group of study patients receiving the same alloSCT in the absence of IL-6R mAb. FINDINGS - Cytokine and pharmacokinetic analysis confirmed transient IL-6 dysregulation in the first month after alloSCT with complete inhibition following IL-6R mAb administration. With median follow up of 497 days, the incidence of grade II-IV GVHD was 12.5% in recipients of IL-6R inhibition (n = 48) versus 41.5% in the (n = 53) control cohort (P = 0.001). Low rates of acute GVHD were noted in patients receiving IL-6R inhibition relative to control patients following both myeloablative (12.5% vs. 46.4%, P = 0.03) and RIC (12.5% vs. 36.0%, P = 0.04). The incidence of severe (grade III/IV) acute GVHD was 4.2% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.012). Relapse and chronic GVHD were unchanged. Immune reconstitution was preserved in recipients of IL-6R inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION - IL-6 is the principal detectable and dysregulated cytokine secreted after alloSCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution and a sustained graft-versus-leukemia effect. Single colour, Illumina Human HT12v4 Beadarrays.
2014-09-09 | E-GEOD-61201 | biostudies-arrayexpress