DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors

10509 Background: Relapses from high-risk tumors pose a major clinical challenge in pediatric oncology. The German INFORM registry (INdividualized therapy FOr Relapsed Malignancies in children) addresses this problem using integrated next-generation sequencing to rapidly identify patient-specific therapeutic targets. Methods: Whole-exome, low-coverage whole-genome and RNA sequencing is complemented with microarray-based DNA methylation profiling. Identified alterations are discussed and prioritized according to biological significance and potential druggability in a weekly molecular tumor board. Results: To date, 214 tumor samples of high-risk pediatric cancer patients have been profiled from 47 German centers, with 39% being sarcomas, 30% brain tumors, 13% neuroblastoma and 18% hematological or other malignancies. Turnaround time from tissue arrival to molecular results was 21 calendar days on average. In 14/214 patients (7%) we identified an underlying germline predisposition syndrome. In several cases there were discrepancies between the original histological diagnosis and our molecular findings, especially in brain tumors. We detected one or more potentially druggable alterations in 147/214 (69%) cases. Tyrosine kinases, the PI3K/mTOR pathway, MAPK pathway, and cell-cycle as well as transcriptional regulators were commonly affected. Based on these findings, targeted therapeutics were incorporated into the therapy regime in one-third of patients, with anecdotal reports of marked responses, including a patient with a pleomorphic sarcoma, where we detected a previously undescribed RAF-fusion, showing a partial remission upon RAF-inhibition. Conclusions: In summary, real-time comprehensive profiling of pediatric tumors provides valuable diagnostic information and identifies potential therapeutic targets. In parallel, the implementation of a systematic program for reverse-translational evaluation is ongoing. Recently, this nationwide effort has expanded to include patients from other countries. We will also recruit patients to the complementary eSMART and INFORM2 biomarker-driven, phase I/II combination trial series, to provide unprecedented access to targeted therapies in Europe.

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PATH-24. MOLECULAR CLASSIFICATION OF HIGH RISK INFANT EMBRYONAL BRAIN TUMORS ENROLLED IN THE ACNS0334 TRIAL: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP

Neuro-Oncology ◽

10.1093/neuonc/noaa222.659 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii429-iii429

Author(s):

Bryan K Li ◽

Peter Burger ◽

Alexander R Judkins ◽

Ben L B Ho ◽

Guolian Kang ◽

...

Keyword(s):

High Risk ◽

Brain Tumors ◽

Significant Proportion ◽

High Grade Glioma ◽

Clinical Analysis ◽

Phase Iii ◽

High Risk Infant ◽

Global Methylation ◽

Molecular Features ◽

Embryonal Brain

Abstract Young children with embryonal brain tumors including medulloblastoma (MB), supratentorial primitive neuro-ectodermal tumor, or pineoblastoma have historically been considered high-risk patients with poor outcomes despite the use of intensive radiation-sparing treatment. In the ACNS0334 phase III trial, 91 consented children <36 months old with the above diagnoses were randomized to intensive induction chemotherapy with or without methotrexate followed by consolidation with stem cell rescue. Here we present the results of a centralized integrated molecular analysis including global methylation profiling (65/91), and whole exome sequencing of tumor (46/91) and germline (35/91) DNA. Unsupervised clustering analyses of methylation profiles using multiple orthogonal methods against a reference dataset of 1200 pediatric brain tumors, revealed known and new molecular entities. For tumors diagnosed as MB on central pathology review, 7.3% (3/41) had a non-MB molecular diagnosis (2 embryonal tumor with multiple rosettes/ETMR, 1 group MYC pineoblastoma), with the remainder as MB Group SHH (11/41), Group3 (25/41), and Group4 (2/41). Among histologic non-MBs, 3/24 (12.5%) were molecular entities not intended for trial inclusion (1 each for ATRT, pleomorphic xanthoastrocytoma, and high-grade glioma). ETMR, historically considered a rare entity, was molecularly identified in a significant proportion (14/65; 21.5%) of samples. Among MB-SHH, we detected deleterious PTCH1 mutations in 6/9 tumors but none among 5 germline samples tested; a germline SUFU frameshift mutation with tumor LOH was also observed in MB-SHH. Correlation of these and other molecular features to the parallel clinical analysis will yield important markers of risk stratification and predictors of treatment response.

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DEV-04. FEASIBILITY AND TOXICITY OF DAILY CARBOPLATIN DURING CRANIOSPINAL IRRADIATION FOR HIGH RISK PEDIATRIC EMBRYONAL BRAIN TUMORS: FIRST REPORT FROM A MIDDLE INCOME COUNTRY

Neuro-Oncology ◽

10.1093/neuonc/noy059.079 ◽

2018 ◽

Vol 20 (suppl_2) ◽

pp. i45-i45

Author(s):

Carlos Leal-Cavazos ◽

Michelle Gutierrez-Herrera ◽

David Hernández-Barajas ◽

Manuel De la O-Cavazos

Keyword(s):

High Risk ◽

Brain Tumors ◽

Middle Income Country ◽

Income Country ◽

Craniospinal Irradiation ◽

Middle Income ◽

First Report ◽

Embryonal Brain

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The impact on outcomes by using thiotepa in tandem transplant for pediatric high-risk embryonal brain tumors

Journal of the Chinese Medical Association ◽

10.1097/jcma.0000000000000018 ◽

2019 ◽

Vol 82 (2) ◽

pp. 148-154

Author(s):

Hsiu-Ju Yen ◽

Ting-Yen Yu ◽

Chih-Ying Lee ◽

Giun-Yi Hung ◽

Tzeon-Jye Chiou ◽

...

Keyword(s):

High Risk ◽

Brain Tumors ◽

Embryonal Brain ◽

The Impact

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Long non-coding RNAs in brain tumors

NAR Cancer ◽

10.1093/narcan/zcaa041 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Keisuke Katsushima ◽

George Jallo ◽

Charles G Eberhart ◽

Ranjan J Perera

Keyword(s):

Gene Expression ◽

Brain Tumors ◽

Brain Cancer ◽

Regulation Of Gene Expression ◽

Therapeutic Targets ◽

Diagnostic Biomarkers ◽

Cancer Pathogenesis ◽

Current State ◽

Non Coding Rnas ◽

Post Transcriptional Regulation

Abstract Long non-coding RNAs (lncRNAs) have been found to be central players in the epigenetic, transcriptional and post-transcriptional regulation of gene expression. There is an accumulation of evidence on newly discovered lncRNAs, their molecular interactions and their roles in the development and progression of human brain tumors. LncRNAs can have either tumor suppressive or oncogenic functions in different brain cancers, making them attractive therapeutic targets and biomarkers for personalized therapy and precision diagnostics. Here, we summarize the current state of knowledge of the lncRNAs that have been implicated in brain cancer pathogenesis, particularly in gliomas and medulloblastomas. We discuss their epigenetic regulation as well as the prospects of using lncRNAs as diagnostic biomarkers and therapeutic targets in patients with brain tumors.

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PATH-08. THE IMPORTANCE OF RE-DIAGNOSIS OF TUMORS PREVIOUSLY CLASSIFIED AS CENTRAL NERVOUS SYSTEM PRIMITIVE NEUROECTODERMAL TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.644 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii426-iii426

Author(s):

Naohide Fujita ◽

Osamu Akiyama ◽

Akihide Kondo

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Tumors ◽

Easy Access ◽

Molecular Analyses ◽

Primitive Neuroectodermal Tumors ◽

Neuroectodermal Tumors ◽

Sanger Sequence ◽

Embryonal Brain ◽

Polymerase Chain

Abstract BACKGROUND The recent molecular analyses have revealed that central nervous system primitive neuroectodermal tumors (CNS PNETs) those having clusters of small round tumor cells are genetically different tumors. However, the concepts of CNS PNET are complicated, and it is difficult to diagnose them appropriately in clinical field. To overcome this difficulty, we reviewed previous studies associated with CNS PNETs, and carried out several approaches, those are relatively easy access to use in clinics, for our 8 samples of embryonal brain tumors diagnosed CNS PNETs in our institution, initially. METHODS We used in combination with immunohistochemistry (IHC), Sanger sequence, Pyrosequence, polymerase chain reaction (PCR), real time PCR and copy number analysis referring recent reports. RESULTS In terms of the diagnosis three out of 8 cases were changed based on the results in this study from previous diagnoses. CONCLUSION In this review, it seemed that either the histopathological evaluation or molecular analyses would be not enough to make accurate diagnosis of CNS embryonal brain tumors, and it is essential to combine both of them including recent comprehensive analysis methods.

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VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells

Peptides ◽

10.1016/j.peptides.2016.01.014 ◽

2016 ◽

Vol 78 ◽

pp. 30-41 ◽

Cited By ~ 3

Author(s):

Madryssa de Boisvilliers ◽

Florian Perrin ◽

Salima Hebache ◽

Annie-Claire Balandre ◽

Souheyla Bensalma ◽

...

Keyword(s):

High Risk ◽

Neuroblastoma Cells ◽

Therapeutic Targets

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Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB)

Bioengineering ◽

10.3390/bioengineering5040096 ◽

2018 ◽

Vol 5 (4) ◽

pp. 96 ◽

Cited By ~ 5

Author(s):

Anders Bailey ◽

Amreena Suri ◽

Pauline Chou ◽

Tatiana Pundy ◽

Samantha Gadd ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Tumors ◽

Meta Analysis ◽

P Value ◽

Embryonal Tumors ◽

Expression Levels ◽

Embryonal Brain

Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB.

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