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Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat [high throughput sequencing]

ABSTRACT: Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat [high throughput sequencing]

PROVIDER: PRJNA625217 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11541488.fastq.gz	Fastqsanger.gz
	SRR11541489.fastq.gz	Fastqsanger.gz
	SRR11541490.fastq.gz	Fastqsanger.gz
	SRR11541491.fastq.gz	Fastqsanger.gz
	SRR11541492.fastq.gz	Fastqsanger.gz

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Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat [array]

Project description:Despite the anticancer activity of pan-histone deacetylase (HDAC) inhibitors, their clinical use has been limited due to toxicity. However, the development of more specific inhibitors that selectively inhibit individual HDACs is emerging as a novel and well-tolerated alternative. Here, we present the results of the first clinical trial evaluating the activity of ricolinostat (the leading HDAC6 inhibitor) in breast cancer (BC) patients. We have developed a computational network-based algorithm to evaluate the activity of the HDAC6 protein, based on the enrichment of its transcriptional targets in differentially expressed genes (HDAC6 score). Through preclinical in vitro and in vivo studies, we confirmed that the HDAC6 score can stratify the sensitivity of BC cells to ricolinostat treatment and may thus have value as a predictive biomarker. Moreover, analysis of ~3,000 primary human breast cancers showed that ~30% of them present high HDAC6 scores. Based on these results, we designed a phase Ib clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in metastatic BC patients. Study results showed that the two agents can be safely combined, that clinical activity is identified specifically in patients with HR+/HER2- disease, and that the HDAC6 score was predictive of response. Expansion of our analysis to other tumor types identified multiple cohorts enriched in high HDAC6 score samples. These results suggest that the HDAC6 score may provide an effective predictive biomarker of ricolinostat sensitivity in multiple human cancers.

2023-02-09 | GSE180606 | GEO

Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat [high throughput sequencing]

2021-04-14 | GSE148623 | GEO

Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat

Project description:Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat

| PRJNA748773 | ENA

Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat [array]

Project description:Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat [array]

| PRJNA748775 | ENA

Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-07-23 | GSE180607 | GEO

Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer.

Project description:Inhibiting individual histone deacetylase (HDAC) is emerging as well-tolerated anticancer strategy compared with pan-HDAC inhibitors. Through preclinical studies, we demonstrated that the sensitivity to the leading HDAC6 inhibitor (HDAC6i) ricolinstat can be predicted by a computational network-based algorithm (HDAC6 score). Analysis of ~3,000 human breast cancers (BCs) showed that ~30% of them could benefice from HDAC6i therapy. Thus, we designed a phase 1b dose-escalation clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in patients with metastatic BC (MBC) (NCT02632071). Study results showed that the two agents can be safely combined, that clinical activity is identified in patients with HR+/HER2- disease and that the HDAC6 score has potential as predictive biomarker. Analysis of other tumor types also identified multiple cohorts with predicted sensitivity to HDAC6i's. Mechanistically, we have linked the anticancer activity of HDAC6i's to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells.

| S-EPMC9992270 | biostudies-literature

Epigenetic remodeling via HDAC6 inhibition amplifies anti-tumoral immune responses in pediatric AML [RNA-seq]

Project description:Histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic target in cancer due to its immunomodulatory effects. While its prognostic significance remains debated, we demonstrate that HDAC6 loss significantly impairs myeloid leukemia progression in vivo, despite having no functional impact on leukemia cell proliferation in vitro. Proteome and secretome profiling of HDAC6-knockout (KO) cells revealed upregulation of several immune-related modulators, including RNase T2, a tumor suppressor known to modulate the tumor microenvironment. RNase T2 upregulation upon HDAC6 loss was restricted to myeloid but not B-ALL cells. Pharmacological inhibition of HDAC6 recapitulated this phenotype, leading to RNase T2 upregulation in myeloid leukemia cells. ATAC-seq revealed increased chromatin accessibility of RNase T2 following HDAC6 loss, highlighting a functionally epigenetic regulatory contribution. Further functional assays conducted in an immunocompetent setting both ex vivo and in vivo demonstrated that HDAC6 inhibition sensitized murine AML cells to broad CD8+ T cell activation as evidenced by increased TNFα and CD107a expression. Consistently, in a syngeneic AML model, HDAC6 inhibition restricted AML cell growth. Moreover, an extended drug screening analysis identified Cytarabine and Clofarabine as significantly synergizing with HDAC6 inhibitor Ricolinostat in AML cell lines or pediatric patient derived PDX-AML cells, while showing limited synergy in ALL cell lines, PDX-ALL cells or healthy controls. These findings establish HDAC6 inhibition as a dual-modality therapeutic strategy in myeloid leukemia, enhancing both immune activation and chemosensitivity.

2025-05-23 | GSE297366 | GEO

Epigenetic remodeling via HDAC6 inhibition amplifies anti-tumoral immune responses in pediatric AML [ATAC-seq]

2025-05-23 | GSE297364 | GEO

Ricolinostat promotes the generation of megakaryocyte progenitors from human hematopoietic stem and progenitor cells

Project description:Ex vivo production of induced megakaryocytes (MKs) and platelets from stem cells is an alternative approach for supplying transfusible platelets. However, it is still difficult to generate large numbers of MKs and platelets from cord blood hematopoietic stem cells. To optimize the differentiation efficiency of megakaryocytic cells from hematopoietic stem and progenitor cells (HSPCs), we first employed a platelet factor 4 (PF4)-promoter reporter and high-throughput screening strategy to screen for small molecules. We found that a small molecule, Ricolinostat, efficiently promoted the generation of CD34+CD41+ megakaryocyte progenitor cells (MkPs) and CD41+CD61+ MKs from cord blood HSPCs. Ricolinostat showed the capacity to enhance the cell fate commitment of MkPs from HSPCs and promoted the proliferation of CD34+CD41+ MkPs. Ricolinostat significantly increased the gene expression levels of key MK transcriptional factors, including HOXC6 and PCGF2. Notably, these megakaryocytic cells generated from Ricolinostat-induced HSPCs could differentiate into mature MKs and platelets. Additionally, RNA sequencing data suggested that Ricolinostat might enhance MkP fate mainly by inhibiting the secretion of IL-8 and decreasing the expression of IL-8 receptor CXCR2. Our study will help in the development of manufacturing protocols for large-scale generation of induced MKs and platelets for clinical application.

2022-02-09 | GSE182181 | GEO

Acetylome Profiling Reveals the Endogenous Substrates of HDAC6

Project description:HDAC6 inhibitors are novel targeted therapies showing good clinical response in a variety of different malignancies. However, their use and farther development is hampered by the limited knowledge regarding what are the endogenous substrates of HDAC6 enzyme. Here we plan to complete acetylome profiling of HAP1 cells with and without HDAC6 knockout to identify which are the HDAC6 substrates and what are the differences between the wildtype and HDAC6-KO cells.

2022-11-09 | PXD026010 | Pride

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