MEK/MELK inhibition and blood–brain barrier deficiencies in atypical teratoid/rhabdoid tumors

Meel, Michaël H.; Navarro, Míriam Guillén; Gooijer, Mark C. de; Metselaar, Dennis S.; Waranecki, Piotr; Breur, Marjolein; Lagerweij, Tonny; Wedekind, Laurine E.; Köster, Jan; Wetering, M. D. van de; Meeteren, Netteke Schouten-van; Aronica, Eleonora; Tellingen, Olaf van; Bugiani, Marianna; Phoenix, Timothy N.; Kaspers, Gertjan J. L.; Hulleman, Esther

doi:10.1093/neuonc/noz151

Cited by 23 publications

(23 citation statements)

References 30 publications

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“…Zhang et al and Wang et al used different genetic and chemical tools (RNA interference, CRISPR, or small -molecule inhibitors) to demonstrate the dependency of MELK in tumor progression [16,58]. Nonetheless, more researchers still tend to verify the roles of MELK in tumor by using RNA interferences and small molecule inhibitors [59,60]. Wang et al also demonstrate that both tools (RNA interference and CRISPR) can be used to illuminate the requirement of MELK in clonogenic cell growth [58].…”

Section: Discussionmentioning

confidence: 99%

MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway

Zhou

et al. 2020

EBioMedicine

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Background: Endometrial carcinoma (EC) is one of the most common gynecological malignancies among women. Maternal embryonic leucine Zipper Kinase (MELK) is upregulated in a variety of human tumors, where it contributes to malignant phenotype and correlates with a poor prognosis. However, the biological function of MELK in EC progression remains largely unknown. Methods: We explored the MELK expression in EC using TCGA and GEO databases and verified it using clinical samples by IHC methods. CCK-8 assay, colony formation assay, cell cycle assay, wound healing assay and subcutaneous xenograft mouse model were generated to estimate the functions of MELK and its inhibitor OTSSP167. qRT-PCR, western blotting, co-immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assay were performed to uncover the underlying mechanism concerning MELK during the progression of EC. Findings: MELK was significantly elevated in patients with EC, and high expression of MELK was associated with serous EC, high histological grade, advanced clinical stage and reduced overall survival and disease-free survival. MELK knockdown decreased the ability of cell proliferation and migration in vitro and subcutaneous tumorigenesis in vivo. In addition, high expression of MELK could be regulated by transcription factor E2F1. Moreover, we found that MELK had a direct interaction with MLST8 and then activated mTORC1 and mTORC2 signaling pathway for EC progression. Furthermore, OTSSP167, an effective inhibitor, could inhibit cell proliferation driven by MELK in vivo and vitro assays. Interpretation: We have explored the crucial role of the E2F1/MELK/mTORC1/2 axis in the progression of EC, which could be served as potential therapeutic targets for treatment of EC.

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Section: Discussionmentioning

confidence: 99%

MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway

Zhou

et al. 2020

EBioMedicine

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“…Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor of the central nervous system (CNS), that is mostly discovered in infancy and young children, and is extremely rare in adults (1). It was firstly named by Rorke et al (2) and was defined to be a grade IV tumor according to the 2016 World Health Organization classification of CNS tumors (3).…”

Section: Introductionmentioning

confidence: 99%

Atypical Teratoid/Rhabdoid Tumor Originated From the Trigeminal Nerve in a Young Male Adult: Case Report and Review of the Literature

Chen

Mei

et al. 2020

Front. Neurol.

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Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm predominantly found in children under the age of 3 years, and is extremely rare in adults. There is no specific clinical presentations or radiological features in reported cases of AT/RT. Diagnosis of brain AT/RT is mainly dependent on the classical pathological characteristics. We report a rare case of AT/RT arising from the trigeminal nerve and leading to progressively multiple cranial nerve palsies in a 25-year-old male patient. Microsurgical resection of the tumor has been performed and confirmed the diagnosis by postoperative pathology. To our knowledge, this is the second case of adult-onset AT/RT originating from the trigeminal nerve.

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“…The overall median survival is 17 months [78]. Improvement of treatment protocols has resulted in only a small increase of survival, as only a subset of patients respond to treatment [77,79,80]. MRI images of AT/RT patients show contrast enhancement, indicating BBB disruption [79,81].…”

Section: Atypical Teratoid/rhabdoid Tumormentioning

confidence: 99%

“…However, little is known about the BBB/BTB and the vasculature in AT/RT. Only one paper has been published on the vasculature and BBB alterations in AT/RT, showing a significant decrease in vessel density and an increase in vessel diameter of the tumor vasculature [79]. Endothelial cells in existing blood vessels maintained expression of claudin-5 but showed displacement of claudin-5 localization compared with healthy tissue [79].…”

Section: Atypical Teratoid/rhabdoid Tumormentioning

confidence: 99%

“…In neovasculature, expression of claudin-5 was lost. In contrast, glucose transporter 1 (GLUT1) was lost in both existing endothelial cells as well as in neovasculature [79]. In order to improve median survival, more research is needed to determine to what extent the BBB/BTB is compromised, and how this can be used for efficient drug delivery.…”

Section: Atypical Teratoid/rhabdoid Tumormentioning

confidence: 99%

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Overview of Current Drug Delivery Methods Across the Blood–Brain Barrier for the Treatment of Primary Brain Tumors

et al. 2020

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Existing drug delivery methods have not led to a significant increase in survival for patients with malignant primary brain tumors. While the combination of conventional therapies consisting of surgery, radiotherapy, and chemotherapy has improved survival for some types of brain tumors (e.g., WNT medulloblastoma), other types of brain tumors (e.g., glioblastoma and diffuse midline glioma) still have a poor prognosis. The reason for the differences in response can be largely attributed to the blood-brain barrier (BBB), a specialized structure at the microvasculature level that regulates the transport of molecules across the blood vessels into the brain parenchyma. This structure hampers the delivery of most chemotherapeutic agents for the treatment of primary brain tumors. Several drug delivery methods such as nanoparticles, convection enhanced delivery, focused ultrasound, intranasal delivery, and intra-arterial delivery have been developed to overcome the BBB in primary brain tumors. However, prognosis of most primary brain tumors still remains poor. The heterogeneity of the BBB in primary brain tumors and the distinct vasculature of tumors make it difficult to design a drug delivery method that targets the entire tumor. Drug delivery methods that combine strategies such as focused ultrasound and nanoparticles might be a more successful approach. However, more research is needed to optimize and develop new drug delivery techniques to improve survival of patients with primary brain tumors.

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MEK/MELK inhibition and blood–brain barrier deficiencies in atypical teratoid/rhabdoid tumors

Cited by 23 publications

References 30 publications

MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway

MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway

Atypical Teratoid/Rhabdoid Tumor Originated From the Trigeminal Nerve in a Young Male Adult: Case Report and Review of the Literature

Overview of Current Drug Delivery Methods Across the Blood–Brain Barrier for the Treatment of Primary Brain Tumors

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