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Michael Hananja Meel

Michael Hananja Meel
Princess Máxima Center for Pediatric Oncology

MD, PhD
Postdoctoral researcher pediatric oncology

About

36
Publications
2,796
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351
Citations
Citations since 2017
33 Research Items
325 Citations
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2017201820192020202120222023020406080
2017201820192020202120222023020406080

Publications

Publications (36)
Article
Full-text available
In recent years, the discovery and development of clustered regularly interspaced short palindromic repeats (CRISPR) technology has revolutionized and accelerated functional genetic screening in cancer research. In this review, we discuss different methods of executing CRISPR screens, with a focus on pediatric tumour entities. Historically, these t...
Article
Full-text available
Diffuse midline gliomas (DMG) are highly aggressive pediatric brain tumors with a grim prognosis. A lack of effective treatment options highlights the critical need to investigate new therapeutic strategies. This includes the use of immunotherapy, which has shown promise in other hard-to-treat tumors. To facilitate immunotherapeutic research in thi...
Article
Full-text available
Background Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. A lack of effective treatment options highlights the need to investigate novel therapeutic strategies. This includes the use of immunotherapy, which has shown promise in other hard-to-treat tumors. To facilitate preclinical immunotherapeutic research, im...
Article
Full-text available
Background Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. A lack of effective treatment options highlights the need to investigate novel therapeutic strategies. This includes the use of immunotherapy, which has shown promise in other hard-to-treat tumors. To facilitate preclinical immunotherapeutic research, im...
Article
Full-text available
Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. In this study, we show that Aurora Kinase A (AURKA) is overexpressed in DMG and can be used as a therapeutic target. Additionally, AURKA inhibition combined with CRISPR/Cas9 screening in DMG cells, revealed Polo-Like Kinase 1 (PLK1) as a synergistic target with AUR...
Article
Full-text available
The blood-brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using pat...
Article
Full-text available
Pediatric high-grade gliomas (pHGG) are malignant brain tumors with a high mortality rate. Radiotherapy (RT) is one of the cornerstones of current pHGG treatment, while the efficacy of chemotherapeutics remains inferior. The use of chemotherapeutics that specifically sensitize tumor cells to irradiation are poorly understood, but may help to increa...
Article
Full-text available
Atypical Teratoid Rhabdoid Tumors (ATRT) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. ATRT can be divided into three molecular subgroups of which the Sonic Hedgehog (SHH) subgroup is most prevalent. In this study, we developed and validated a novel patient-derived ATRT model, which we used along a pan...
Article
Full-text available
Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repre...
Article
Background and purpose Effective combination treatments with fractionated radiotherapy rely on a proper understanding of the dynamic responses that occur during treatment. We explored the effect of clinical fractionated radiotherapy on the development and timing of radioresistance in tumor cells. Methods and Materials Different colon (HT29/HCT116/...
Article
Purpose: Diffuse intrinsic pontine glioma (DIPG) is an incurable type of pediatric brain cancer, which in the majority of cases is driven by mutations in genes encoding histone 3 (H3K27M). We here determined the preclinical therapeutic potential of combined AXL and HDAC inhibition in these tumors to reverse their mesenchymal, therapy-resistant, ph...
Article
Full-text available
Background Pediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death during childhood. Due to their diffuse growth characteristics, chemoresistance and location behind the blood-brain barrier (BBB), the prognosis of pHGG has barely improved in the past decades. As such, there is a dire need for new therapies that circumvent...
Article
Full-text available
Background: Atypical teratoid/rhabdoid tumors (AT/RT) are rare, but highly aggressive. These entities are of embryonal origin occurring in the central nervous system (CNS) of young children. Molecularly these tumors are driven by a single hallmark mutation, resulting in inactivation of SMARCB1 or SMARCA4. Additionally, activation of the MAPK signa...
Article
Full-text available
Diffuse midline gliomas (DMG) are rapidly fatal tumors of the midbrain in children, characterized by a diffuse growing pattern and high levels of intrinsic resistance to therapy. The location of these tumors, residing behind the blood-brain barrier (BBB), and the limited knowledge about the biology of these tumors, has hindered the development of e...
Article
Full-text available
Purpose Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autop...
Article
Full-text available
There are two errors and one omission in the original article. Author Gottardo’s correct name is Nicholas G. Gottardo, author Hulleman’s correct affiliation is no. 3 (VUMC, Amsterdam), and the Acknowledgements should include the following sentence: “We would like to thank Dr Angel Montero Carcaboso (Hospital Sant Joan de Deu, Barcelona, Spain) for...
Article
Purpose: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor, for which no effective therapeutic options currently exist. We here determined the potential of inhibition of the maternal embryonic leucine zipper kinase (MELK) for the treatment of DIPG. Experimental design: We evaluated the antitumor efficacy of the...
Article
Full-text available
Pediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death during childhood. Due to their diffuse growth pattern, difficult to reach location during surgery and position behind the blood-brain barrier (BBB), prognosis of pHGG has barely improved, despite decades of research. Celastrol is a naturally occuring compound that cro...
Article
Full-text available
The isocitrate dehydrogenase-1 (IDH1) mutation serves as a hallmark for secondary high-grade gliomas, occurring in over 75% of all secondary glioblastomas (GBM) in adults. IDH1 mutations in pediatric high-grade gliomas are much rarer, and its role is still largely unknown. The lack of biologically representative in vitro and in vivo IDH1 mutant mod...
Article
Full-text available
Maternal embryonic leucine zipper kinase (MELK) is a highly overexpressed kinase in diffuse intrinsic pontine glioma (DIPG). Inhibition of MELK by the small molecule OTSSP167 effectively reduces proliferation and induces cell death in primary DIPG cell lines at low nanomolar concentrations. RNA sequencing of DIPG cells treated with OTSSP167 reveals...
Article
Full-text available
Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant tumors of the central nervous system occurring predominantly in young children. Currently, the only curative therapeutic option consists of surgery combined with intensive chemo- and radiotherapy, often leading to severe long-term sequelae. Therefore, novel therapeutic strategies that r...
Article
Full-text available
Diffuse intrinsic pontine glioma (DIPG) is an incurable type of pediatric brainstem cancer that is thought to originate from primitive neural stem cells, and is characterized by the frequent presence of mutations in histone 3 genes. Biopsy studies have shown that a large subset of DIPG possesses a mesenchymal phenotype, likely contributing to the d...
Article
Full-text available
Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal types of cancer in children. In recent years, it has become evident that these tumors are driven by epigenetic events, mainly mutations involving genes encoding Histone 3, setting them apart from their adult counterparts. These tumors are ex...
Article
Full-text available
Pediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are rare, but rapidly fatal malignancies of the central nervous system (CNS), and the leading cause of cancer-related death in children. Besides the scarcity of available biological material for research, the study of these diseases has been hampered by methodological pr...
Article
Diffuse intrinsic pontine glioma (DIPG) is an aggressive type of brainstem cancer occurring mainly in children, for which there currently is no effective therapy. Current efforts to develop novel therapeutics for this tumor make use of primary cultures of DIPG cells, maintained either as adherent monolayer in serum containing medium, or as neurosph...
Article
Inadequate tumor uptake of the vascular endothelial growth factor (VEGF) antibody bevacizumab could explain lack of effect in diffuse intrinsic pontine glioma (DIPG). Methods: By combining data from a positron emission tomography (PET) imaging study using zirconium-89((89)Zr)-labeled bevacizumab and an autopsy study, a 1-on-1 analysis of multiregio...
Article
Full-text available
The isocitrate dehydrogenase 1 (IDH1) mutation serves as a hallmark for secondary high-grade gliomas, occurring in approximately 80% of all secondary glioblastomas (GBM) in adults. IDH1 mutations in pediatric high-grade gliomas are much rarer, and its role is still largely unknown. The lack of biologically representative in vitro and in vivo IDH1 m...
Article
Full-text available
Pediatric high-grade gliomas (HGGs) are the leading cause of cancer related death during childhood. Recent insights revealed that the epigenetic landscape of HGGs in children shows a distinct pattern from their adult counterparts, as has been shown with pediatric HGG associated H3K27M and H3G34V/R histone modifications. These findings highlight the...
Article
Full-text available
Maternal embryonic leucine zipper kinase (MELK) is the second highest expressed kinase in diffuse intrinsic pontine glioma (DIPG). Inhibition of MELK by the small molecule OTSSP167 effectively reduces proliferation and induces cell death in primary DIPG cell lines at low nanomolar concentrations. RNA sequencing of DIPG cells treated with OTSSP167 r...
Article
Full-text available
Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant tumors that occur both in- and outside the central nervous system, predominantly in young children. Although therapeutic interventions, combining surgery with intensive chemotherapy and conformal radiotherapy, have shown curative potential, the long-term consequences of these treatment...
Article
OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of d...
Article
Full-text available
Persistence of leukemic stem cells (LSC) after chemotherapy is thought to be responsible for relapse and prevents the curative treatment of acute myeloid leukemia (AML) patients. LSC and normal hematopoietic stem cells (HSC) share many characteristics and co-exist in the bone marrow of AML patients. For the development of successful LSC-targeted th...
Article
Only a minority of cells, the leukemic stem cells (LSC), within AML are responsible for tumor growth and maintenance. Many patients experience relapse after therapy which originates from outgrowth of therapy resistant LSC. Therefore, eradication of LSC is necessary to cure AML. Both the normal hematopoietic stem cells (HSC) and LSC co-exist in the...

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