Effects of a cytokine inhibitor, JTE-607, on the response to endotoxin in healthy human volunteers

Borozdenkova, Svetlana; Mant, Timothy; Allen, Edward D.; Pu, Kewei; Hoshino, Shoji; Jurčević, Stipo

doi:10.1016/j.intimp.2011.07.013

Cited by 8 publications

(10 citation statements)

References 50 publications

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“…JTE-607 was first identified over 20 years ago as a cytokine synthesis inhibitor; however, the direct molecular target remained elusive. Despite the lack of a defined mechanism, JTE-607 was tested in a Phase I dose-escalation trial in healthy human volunteers, with no serious adverse effects (22). Therefore, despite inhibiting an essential enzyme responsible for processing >70% of polyadenylated mRNAs, JTE-607 is not uniformly toxic in humans.…”

Section: Discussionmentioning

confidence: 99%

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone processing

Alahmari

Chaubey

Tisdale

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options. This potentiates the importance of uncovering novel drug targets. We have discovered global dysregulation of the gene regulatory process alternative polyadenylation (APA) in PDAC. APA is a pre-mRNA processing mechanism that generates mRNAs with distinct 3’ ends, impacting gene expression and protein function. We revealed that APA dysregulation in PDAC drives oncogenic signatures and predicts poor patient outcome. As APA directs widespread gene expression dysregulation across the PDAC patient population, we hypothesized that inhibition of APA has therapeutic potential. APA is controlled by a complex of proteins, including cleavage and polyadenylation specificity factor 3 (CPSF3). CPSF3 is the endonuclease catalyzing mRNA cleavage, and a potentially druggable target. We now find that CPSF3 is highly expressed and associated with poor prognosis in PDAC patients. CPSF3 knockdown decreases PDAC proliferation and clonogenicity in vitro and tumor growth in vivo. We demonstrate that CPSF3 knockdown induces widespread APA alterations of oncogenes and tumor suppressors, and determine the contribution of one of these events to CPSF3-induced cell proliferation phenotype. Furthermore, we find that PDAC, but not non-transformed pancreatic cells, are sensitive to the CPSF3 small molecule inhibitor JTE-607. Mechanistically, JTE-607 impairs replication-dependent histone processing, disrupting nucleosome assembly and destabilizing chromatin structure. Finally, we determine that JTE-607 attenuates cell proliferation by arresting cells in early S-phase of the cell cycle. Altogether, we identify CPSF3 as a druggable target in PDAC and reveal novel mechanisms by which CPSF3 controls cancer cell growth.SignificanceThis work identifies CPSF3 as a potential drug target in pancreatic ductal adenocarcinoma and reveals new mechanisms by which CPSF3 inhibition attenuates PDAC cell proliferation through modulating alternative polyadenylation and histone processing.

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Section: Discussionmentioning

confidence: 99%

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone processing

Alahmari

Chaubey

Tisdale

et al. 2022

Preprint

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“…This mRNA-processing inhibitor had minimal effects on the release of soluble factors from CAR-T cells, suggesting that it selectively inhibits cytokine production in monocytes (82). An early clinical study found that a single dose of JTE-607 appeared to be welltolerated and reduced the severity of endotoxin-induced inflammation in healthy individuals (83). If this inhibitor can effectively prevent the release of multiple cytokines without effecting the mRNA processing in CAR-T cells and other healthy tissues, it could be more effective than therapies that only target a single cytokine.…”

Section: Current Strategies To Prevent Inflammatory Toxicities During Car-t Cell Therapymentioning

confidence: 99%

CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities

Fischer

Bhattarai

2021

Front. Immunol.

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Engineered T cell therapies such as chimeric antigen receptor (CAR) expressing T cells (CAR-T cells) have great potential to treat many human diseases; however, inflammatory toxicities associated with these therapies present safety risks and can greatly limit its widespread use. This article briefly reviews our current understanding of mechanisms for inflammatory toxicities during CAR T-cell therapy, current strategies for management and mitigation of these risks and highlights key areas of knowledge gap for future research.

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“…Moreover, recent studies have shown that corticosteroids do not influence the efficacy and kinetics of CAR-Ts in the treatment of B-ALL (73). Additionally, TO-207 is an investigational drug that can inhibit the abnormal activation of macrophages and monocytes with no negative effects on the activity of T cells (74)(75)(76)(77). In vitro studies have demonstrated that TO-207 acts as a multi-cytokine inhibitor by suppressing monocyte-mediated secretion of IL-6 and other inflammatory cytokines (including IL-1b, monocyte chemoattractant protein 1 (MCP-1), IL-8, IL-18, and GM-CSF) without deteriorating CAR-T functionality (74,78).…”

Section: Il-1 and Il-6 Blockadementioning

confidence: 99%

Optimizing the Clinical Impact of CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia: Looking Back While Moving Forward

Kozani

Rahbarizadeh

2021

Front. Immunol.

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Chimeric antigen receptor T-cell (CAR-T) therapy has been successful in creating extraordinary clinical outcomes in the treatment of hematologic malignancies including relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). With several FDA approvals, CAR-T therapy is recognized as an alternative treatment option for particular patients with certain conditions of B-ALL, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, or multiple myeloma. However, CAR-T therapy for B-ALL can be surrounded by challenges such as various adverse events including the life-threatening cytokine release syndrome (CRS) and neurotoxicity, B-cell aplasia-associated hypogammaglobulinemia and agammaglobulinemia, and the alloreactivity of allogeneic CAR-Ts. Furthermore, recent advances such as improvements in media design, the reduction of ex vivo culturing duration, and other phenotype-determining factors can still create room for a more effective CAR-T therapy in R/R B-ALL. Herein, we review preclinical and clinical strategies with a focus on novel studies aiming to address the mentioned hurdles and stepping further towards a milestone in CAR-T therapy of B-ALL.

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Effects of a cytokine inhibitor, JTE-607, on the response to endotoxin in healthy human volunteers

Cited by 8 publications

References 50 publications

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone processing

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone processing

CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities

Optimizing the Clinical Impact of CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia: Looking Back While Moving Forward

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