Targeting Aspartate Beta-Hydroxylase with the Small Molecule Inhibitor MO-I-1182 Suppresses Cholangiocarcinoma Metastasis

Nonomura, Katsuya; Ogawa, Kousuke; Ji, Chengcheng; Cao, Kevin; Bai, Xuewei; Mulla, Joud; Cheng, Zhixiang; Wands, Jack R.; Huang, Chiung‐Kuei

doi:10.1007/s10620-020-06330-2

Cited by 7 publications

(6 citation statements)

References 39 publications

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“…ASPH is a highly conserved β-dioxygenase enzyme which is sequestered in normal adult tissues. ASPH is overexpressed in a variety of cancer types, including non-small cell lung, pancreatic, cholangiocarcinoma [ 12 , 19 ], hepatocellular [ 13 ], and colorectal cancer [ 12 ]. ASPH overexpression promotes tumor cell invasion and migration [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…ASPH overexpression promotes tumor cell invasion and migration [ 24 ]. The specific small molecular inhibitor MO-I-1182 inhibits cancer migration and invasion by targeting ASPH [ 11 , 13 , 19 ]. Activation of the Notch cascade by ASPH has been shown to promote tumor progression in BC [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…ASPH has recently been shown to promote BC development and metastasis by activating the Notch cascade [ 11 ]. ASPH is also overexpressed and strongly correlated with tumor invasiveness and poor prognosis in various tumor types, including colorectal [ 12 ], hepatocellular [ 13 ], non-small cell lung [ 14 ], pancreatic [ 15 – 17 ], and prostate cancer [ 18 ], and cholangiocarcinoma [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the Relationship Between the Expression of Aspartate β-Hydroxylase and the Pathological Characteristics of Breast Cancer

Zhang

Gao

et al. 2020

Med Sci Monit

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of the Relationship Between the Expression of Aspartate β-Hydroxylase and the Pathological Characteristics of Breast Cancer

Zhang

Gao

et al. 2020

Med Sci Monit

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“…One gene related to cardiac conduction, ASPH, is highly overexpressed in cholangiocarcinoma(CCA) and HCC [47]. Inhibition of ASPH could decrease CCA development [48]. Another related gene, ITPR2, is the major intracellular calcium release channel in hepatocytes to regulate Calcium (Ca2+) signaling, resulting in regulating lots of function of hepatocytes, including glucose and lipid metabolism, apoptosis, gene transcription, bile secretion, and cell proliferation [49].…”

Section: Plos Computational Biologymentioning

confidence: 99%

ORN: Inferring patient-specific dysregulation status of pathway modules in cancer with OR-gate Network

et al. 2021

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Pathway level understanding of cancer plays a key role in precision oncology. However, the current amount of high-throughput data cannot support the elucidation of full pathway topology. In this study, instead of directly learning the pathway network, we adapted the probabilistic OR gate to model the modular structure of pathways and regulon. The resulting model, OR-gate Network (ORN), can simultaneously infer pathway modules of somatic alterations, patient-specific pathway dysregulation status, and downstream regulon. In a trained ORN, the differentially expressed genes (DEGs) in each tumour can be explained by somatic mutations perturbing a pathway module. Furthermore, the ORN handles one of the most important properties of pathway perturbation in tumours, the mutual exclusivity. We have applied the ORN to lower-grade glioma (LGG) samples and liver hepatocellular carcinoma (LIHC) samples in TCGA and breast cancer samples from METABRIC. Both datasets have shown abnormal pathway activities related to immune response and cell cycles. In LGG samples, ORN identified pathway modules closely related to glioma development and revealed two pathways closely related to patient survival. We had similar results with LIHC samples. Additional results from the METABRIC datasets showed that ORN could characterize critical mechanisms of cancer and connect them to less studied somatic mutations (e.g., BAP1, MIR604, MICAL3, and telomere activities), which may generate novel hypothesis for targeted therapy.

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“…Oncogenic abilities of ASPH have been experimentally demonstrated using tumor cell lines and mouse and rat models of different types of human tumors with ASPH overexpression, including cholangiocarcinoma [4,44,75,87,88], hepatocellular carcinoma [5,37,38,57,62,70,73], neuroblastoma [30], pancreatic cancer [7,41,43,71], glioma [6], breast carcinoma [42], castration-resistant prostate cancer [66], and colorectal cancer [56]. In studies analyzing ASPH function, various approaches were utilized to reveal signaling pathways affected by ASPH.…”

Section: Asph As a Therapeutic Targetmentioning

confidence: 99%

Aspartate β-hydroxylase as a target for cancer therapy

Kanwal

Šmahel

Olsen

et al. 2020

J Exp Clin Cancer Res

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As metastasis is a major cause of death in cancer patients, new anti-metastatic strategies are needed to improve cancer therapy outcomes. Numerous pathways have been shown to contribute to migration and invasion of malignant tumors. Aspartate β-hydroxylase (ASPH) is a key player in the malignant transformation of solid tumors by enhancing cell proliferation, migration, and invasion. ASPH also promotes tumor growth by stimulation of angiogenesis and immunosuppression. These effects are mainly achieved via the activation of Notch and SRC signaling pathways. ASPH expression is upregulated by growth factors and hypoxia in different human tumors and its inactivation may have broad clinical impact. Therefore, small molecule inhibitors of ASPH enzymatic activity have been developed and their anti-metastatic effect confirmed in preclinical mouse models. ASPH can also be targeted by monoclonal antibodies and has also been used as a tumor-associated antigen to induce both cluster of differentiation (CD) 8 + and CD4 + T cells in mice. The PAN-301-1 vaccine against ASPH has already been tested in a phase 1 clinical trial in patients with prostate cancer. In summary, ASPH is a promising target for anti-tumor and anti-metastatic therapy based on inactivation of catalytic activity and/or immunotherapy.

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Targeting Aspartate Beta-Hydroxylase with the Small Molecule Inhibitor MO-I-1182 Suppresses Cholangiocarcinoma Metastasis

Cited by 7 publications

References 39 publications

Characterization of the Relationship Between the Expression of Aspartate β-Hydroxylase and the Pathological Characteristics of Breast Cancer

Characterization of the Relationship Between the Expression of Aspartate β-Hydroxylase and the Pathological Characteristics of Breast Cancer

ORN: Inferring patient-specific dysregulation status of pathway modules in cancer with OR-gate Network

Aspartate β-hydroxylase as a target for cancer therapy

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