Aspartate-β-hydroxylase induces epitope-specific T cell responses in hepatocellular carcinoma

Tomimaru, Yoshito; Mishra, Sasmita; Safran, Howard; Charpentier, Kevin P.; Martin, William; Groot, Anne S. De; Gregory, Stephen H.; Wands, Jack R.

doi:10.1016/j.vaccine.2015.01.037

Cited by 24 publications

(36 citation statements)

References 56 publications

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“…The activation of both cluster of differentiation (CD)4 + T cells and CD8 + cytotoxic T cells (CTLs) is required for a sustained anti-tumor response [59][60][61]. In an experimental murine model, ASPH-loaded dendritic cells (DCs) had a substantial anti-tumor effect on HCC, and both CD4 + and CD8 + cells contributed to these effects [59].…”

Section: Therapeutic Approaches Targeting Asphmentioning

confidence: 99%

“…In an experimental murine model, ASPH-loaded dendritic cells (DCs) had a substantial anti-tumor effect on HCC, and both CD4 + and CD8 + cells contributed to these effects [59]. Furthermore, in peripheral blood mononuclear cells (PBMCs) derived from HCC patients, ASPH protein-loaded DCs could also activate CD4 + T cell and CD8 + CTLs, via ASPH-derived human leukocyte antigen (HLA) class I-and class II-restricted peptides [61]. These findings indicate the usefulness of ASPH as a molecular target in immunotherapy, especially in HCC.…”

Section: Therapeutic Approaches Targeting Asphmentioning

confidence: 99%

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Recent advances in research on aspartate β-hydroxylase (ASPH) in pancreatic cancer: A brief update

Hou

et al. 2018

Bosn J of Basic Med Sci

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Pancreatic cancer (PC) is a highly aggressive tumor, often difficult to diagnose and treat. Aspartate β-hydroxylase (ASPH) is a type II transmembrane protein and the member of α-ketoglutarate-dependent dioxygenase family, found to be overexpressed in different cancer types, including PC. ASPH appears to be involved in the regulation of proliferation, invasion and metastasis of PC cells through multiple signaling pathways, suggesting its role as a tumor biomarker and therapeutic target. In this review, we briefly summarize the possible mechanisms of action of ASPH in PC and recent progress in the therapeutic approaches targeting ASPH.

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Section: Therapeutic Approaches Targeting Asphmentioning

confidence: 99%

Section: Therapeutic Approaches Targeting Asphmentioning

confidence: 99%

Recent advances in research on aspartate β-hydroxylase (ASPH) in pancreatic cancer: A brief update

Hou

et al. 2018

Bosn J of Basic Med Sci

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“…Finally, we conducted in vitro experiments to determine the degree to which treatment of astrocytoma cells with small molecule inhibitors of ASPH’s catalytic activity would be sufficient to decrease cell motility and invasion. The research design was focused on ASPH rather than Humbug because the Type 2 transmembrane structure of ASPH renders its critical catalytic domain accessible to small molecule inhibitor [15, 16] and immune [17, 18] targeting, as demonstrated in other malignancies.…”

Section: Introductionmentioning

confidence: 99%

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

Sturla

Tong

Hebda

et al. 2016

Heliyon

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BackgroundDespite therapeutic advances, survival with glioblastoma multiforme (GBM) remains below 15 months from diagnosis due to GBM’s highly infiltrative nature which precludes complete surgical resection. Patient outcomes could potentially be improved by targeting genes and pathways that drive neoplastic cell motility and invasiveness, including hypoxia-inducible factor-1 (HIF-1α), NOTCH, and aspartate-β-hydroxylase (ASPH).MethodsHuman astrocytoma biopsy specimens (n = 37), WHO Grades II–IV, were analyzed for levels and distributions of ASPH and HIF-1α immunoreactivity by immunohistochemical staining, and ASPH, Notch, JAG, HES1, HEY1 and HIF1α mRNA expression by quantigene multiplex analysis. The effects of small molecule inhibitors on ASPH’s catalytic activity, cell viability and directional motility were examined in vitro in established GBM cell lines and primary tumor cells from an invasive mouse model of GBM.ResultsThe highest grade astrocytoma, i.e. GBM was associated with the highest levels of ASPH and HIF1α, and both proteins were more abundantly distributed in hypoxic compared with normoxic regions of tumor. Furthermore, mining of the TCGA database revealed higher levels of ASPH expression in the mesenchymal subtype of GBM, which is associated with more aggressive and invasive behavior. In contrast, lower grade astrocytomas had low expression levels of ASPH and HIF1α. In vitro experiments demonstrated that small molecule inhibitors targeting ASPH’s catalytic activity significantly reduced GBM viability and directional motility. Similar effects occurred in GBM cells that were transduced with a lentiviral sh-ASPH construct.ConclusionThis study demonstrates that increased ASPH expression could serve as a prognostic biomarker of gliomas and may assist in assigning tumor grade when biopsy specimens are scant. In addition, the findings suggest that GBM treatment strategies could be made more effective by including small molecule inhibitors of ASPH.

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“…The epitope‐specific components required for a peptide‐based candidate vaccine were investigated. Both HLA class I‐ and class II‐restricted peptides derived from ASPH induced T cell activation in HCC, indicating that ASPH protein and related peptides produce the type of cellular immune responses required to generate antitumor activity . Annexin A3 (ANXA3) is preferentially expressed in cancer stem‐like cells/cancer‐initiating cells (CSCs/CICs) derived from HCC cells.…”

Section: Immunotherapeutic Strategiesmentioning

confidence: 99%

Promising new strategies for hepatocellular carcinoma

Nakamoto

2016

Hepatology Research

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Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. It usually arises based on a background of chronic liver diseases, defined as the hypercarcinogenic state. The current treatment options for HCC ranging from locoregional treatments to chemotherapies, including sorafenib, effectively regulate the limited sizes and numbers of the nodules. However, these treatments remain unsatisfactory because they have insufficient antitumor effects on the large and numerous nodules associated with HCC and because of a high recurrence rate in the surrounding inflamed liver. To develop novel and promising therapies with higher antitumor effects, recent progress in identifying molecular targets and developing immunological procedures for HCC are reviewed. The molecular targets discussed include the intracellular signaling pathways of protein kinase B/mammalian target of rapamycin and RAS/RAF/mitogen-activated protein kinase, Wnt/β-catenin and glutamine synthetase, insulin-like growth factor, signal transducer and activator of transcription 3, nuclear factor-κB and telomerase reverse transcriptase, and c-MET. Immunological studies have focused mainly on target identification, T cells, natural killer cells, dendritic cells, natural killer T cells, and vaccine development.

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Aspartate-β-hydroxylase induces epitope-specific T cell responses in hepatocellular carcinoma

Cited by 24 publications

References 56 publications

Recent advances in research on aspartate β-hydroxylase (ASPH) in pancreatic cancer: A brief update

Recent advances in research on aspartate β-hydroxylase (ASPH) in pancreatic cancer: A brief update

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

Promising new strategies for hepatocellular carcinoma

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