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  • NLM标题： Neuro Oncol
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  • 1.

    【2hr】DIPG-32. COMBINATION OF ChIP-SEQ AND RNA-SEQ ANALYSIS FOR TARGET DISCOVERY REVEAL PROMISING CANDIDATES FOR VALIDATION

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    机译 DIPG-32。结合ChIP-SEQ和RNA-SEQ分析进行目标发现揭示可能的候选者
    摘要：INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) has one of the lowest overall survival amongst pediatric brain cancers. DIPG can be stratified into molecular subtypes dictated by histone mutational status: H3.3K27M, H3.1K27M, and H3 wildtype. Mutant histone proteins drive cellular proliferation by reprogramming epigenetic landscape. To interrogate the DIPG epigenome, we performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) in 5 DIPG tumors (H3.3K27M and H3 wildtype) and 3 healthy pons. This is the first report of ChIP-seq in DIPG tissue with H3 wildtype tumor. METHODS: ChIP-Seq was performed on DIPG tumors and control healthy pons for histone modifications indicative of active promoter (H3K4me3), repressive promoter (H3K27me3), and enhancer chromatin (H3K4me1 and H3K27ac). We focused on targets active in both H3K27M and H3 wildtype. Already existing RNA-seq data from DIPG upfront biopsy specimens (n=25) were used to narrow targets with increased transcripts. Immunohistochemistry (IHC) was performed to show protein expression. Human DIPG primary cell lines were assessed using Western blot analysis. RESULTS: Multiple targets were identified from ChIP-seq with activated histone including Notch1, CSPG4, and B7-H3. Focusing on B7-H3, RNA-seq confirmed high transcript levels at 43 Transcripts Per Million (TPM) in DIPG tumor and was significantly elevated compared to adjacent healthy brain at 5.5 TPM (p < 6x10-6). IHC analysis of 3 DIPGs showed strong B7-H3 staining compared to adjacent normal brain. To show the fidelity of preclinical models to human donor, primary DIPG cell lines (n=6) were interrogated by western blot assay. A 4.9 fold increase in B7-H3 (p=0.011) in DIPG cell lines was found when compared to protein lysates from healthy brain tissue (n=3). CONCLUSION: Using primary DIPG tumor tissue for ChIP-Seq analysis is novel and our study shows that epigenetic analysis by ChIP-seq coupled with transcriptional analysis by RNA-seq can be utilized to find new targets for DIPG therapy.
  • 2.

    【2hr】DIPG-31. FEASIBILITY OF HYPERPOLARIZED 13C METABOLIC IMAGING IN PEDIATRIC PATIENTS WITH DIPG AND OTHER CNS CANCERS

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    机译 DIPG-31。患有DIPG和其他中枢神经系统疾病的小儿患者超极化13C代谢成像的可行性
    摘要：INTRODUCTION: As DIPG-tailored therapies become available in the future, the pediatric oncology community will need to address a longstanding issue regarding the lack of imaging biomarkers for evaluating response to treatment. Dynamic hyperpolarized carbon-13 ( C) MR imaging offers a non-invasive means of probing real-time metabolism and has already been applied in adult patients with glioma (Park et al., 2018; Keshari 2018). The purpose of the current work was to evaluate the feasibility of this technique in pediatric patients and compare metabolism in normal-appearing white matter (NAWM) with adults. METHODS: Six pediatric patients (1 female, 5 males; ages 9–17) previously diagnosed with DIPG ( =3), pineoblastoma ( =1), medulloblastoma ( =1), or adamantinomatous craniopharyngioma ( =1) received dynamic C MR imaging exams following intravenous injection of hyperpolarized [1- C]pyruvate at 1–3 mL/s (0.43mL/kg). MR sequences consisted of either echo-planar imaging or echo-planar spectroscopic imaging, with 3.38-8cm spatial resolution and 3s temporal resolution. Pre/post-injection EKGs and continuous vital sign measurements enabled close monitoring of patient response to the hyperpolarized contrast agent. All patients had previous radiation treatment (50-60Gy) and underwent diverse therapies; only 2 patients (DIPG) were surgery-naive. Conversion of [1- C]pyruvate to [1- C]lactate was kinetically modeled as a rate constant (k ) in NAWM using established methodology. RESULTS: There were no adverse effects in patients following injection of [1- C]pyruvate. The apparent rate constant (k ) in this pediatric cohort was 0.022±0.007s (range:0.014–0.030s ), which was similar to adult patients with glioma treated by radiation (0.021±0.005). In one surgery-naïve patient with DIPG who received a higher resolution exam, two adjacent voxels in the T lesion demonstrated a 176–220% increase in k relative to NAWM. CONCLUSION: Initial results suggest hyperpolarized C MR imaging can be safely performed in pediatric patients with CNS cancers and may augment treatment surveillance.
  • 3.

    【2hr】DIPG-30. ISOFORM SPECIFIC OVEREXPRESSION OF WILMS’ TUMOR PROTEIN IN DIFFUSE INTRINSIC PONTINE GLIOMAS

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    机译 DIPG-30。弥散性内源性胶质神经胶质瘤中威尔姆氏肿瘤蛋白的ISOFORM特异性过表达
    摘要：Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brain cancer constituting 10–15% of all central nervous system (CNS) tumors in children. Its anatomical location and infiltrative nature make it one of the most challenging tumors to treat. As such, targeted therapies are gaining more interest in CNS tumors. To identify a suitable therapeutic target, we evaluated publicly available gene expression data of pediatric glioblastoma specimens (n=34, ), DIPG specimens (n=35, ) and gene expression data of DIPG specimens from our previous dataset (n=5). Further analysis using 37 pediatric midline glioma specimens collected at autopsy in accordance with Children’s National Health System Institutional Review Board approval, indicated overexpression of one candidate protein, Wilms’ tumor protein (WT1), by immunohistochemistry. Interestingly, our immunohistochemistry and immunofluorescence analysis showed that WT1 in DIPG specimens is localized in the cytoplasm. Real-Time Quantitative Reverse Transcription PCR analysis using fresh frozen tumor specimens also showed that H3.3K27M-DIPG subtypes (n=3) to express higher levels of WT1 protein compared to those with H3.1K27M (n=2) (5.3 fold). More importantly, RNA-seq analysis of DIPG tumors (n=23) revealed specific transcriptome expression of WT1 transcript variant F. Nuclear export signal prediction analysis of the WT1 protein sequence translated by this transcript showed a higher nuclear export signal prediction score compared to other isoforms of WT1. Our findings suggest that WT1, particularly WT1 variant F, is a robust tumor specific antigen in DIPG, which may reveal its biological role in tumorigenesis and may have implications for clinical translation as an immunotherapeutic target.
  • 4.

    【2hr】DIPG-36. CLINICAL, RADIOLOGICAL, AND HISTO-MOLECULAR CHARACTERISTICS OF DIFFUSE INTRINSIC PONTINE GLIOMA IN PATIENTS WHO SURVIVE LESS THAN 3 MONTHS FROM DIAGNOSIS: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY

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    机译 DIPG-36。生存期少于3个月的患者弥散性内源性胶质神经胶质瘤的临床，放射学和组织学特征：国际DIPG注册机构的报告
    摘要：Diffuse intrinsic pontine glioma (DIPG) is aggressive brainstem tumor with median survival of < 1 year. We queried data from the International DIPG Registry to define clinical, radiological, histological, and molecular characteristics of DIPG patients who survived < 3 months from diagnosis. Among 909 patients enrolled on the registry, 59 (6.5%) had overall survival (OS) of < 3 months. Median age at diagnosis was 5.8 years (range 0–13 years), and 12 (20%) were age < 3 years at diagnosis. Most presented with short duration of symptoms (< 6 weeks, 50/58; 86%) and at least one cranial nerve palsy, cerebellar sign, and/or pyramidal tract sign (52/54; 96%). Twenty-two (41%) presented with hydrocephalus, including 10 who required CSF diversion. All had extra-pontine extension on diagnostic imaging. Less than half of patients (25/56, 45%) received therapy; of these, 11 received radiation (RT) only, 12 received RT and chemotherapy, and 2 received chemotherapy only. Most received steroids (48/52; 92%), including 27 who received palliative steroids at the end of life. Biopsy and autopsy were performed in 11/57 (19%) and 13/58 (22%) cases, respectively. Of 22 for whom histology was known, 19 represented high-grade glioma subtypes, 2 low-grade gliomas, and 1 embryonal tumor. Six were molecularly characterized, and 3 harbored H3K27M mutations. Ongoing work will aim to further characterize the molecular features of these tumors with exceptional poor outcomes despite therapy.
  • 5.

    【2hr】DIPG-34. PRECLINICAL PRECISION TESTING OF PNOC003 BIOPSY DERIVED MODELS OF DIPG

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    机译 DIPG-34。 PNOC003生物活检模型DIPG的临床前精密度测试
    摘要：RATIONALE: One of the major hurdles in developing effective treatment for children with DIPG includes the lack of extensive combinatorial studies targeting major driver oncogenic pathways. Combination of H3K27M and TP53 mutations are found in over 50% of DIPG tumors, however, there is a lack of effective combinatorial precision therapy. METHODS: Tissue specimens obtained from subjects with DIPG were used to generate preclinical models. Subjects were enrolled in a prospective molecular diagnostic clinical trial and specimens were obtained by surgical biopsy both at initial diagnosis, and at the time of progression. RESULTS: Fourteen primary neurosphere cell lines and nine xenograft mouse models were successfully generated. The success rate of generating primary neurospheres and xenograft models was 45% and 75%, respectively. Among the 14 cell lines, one was derived from a biopsy performed after tumor progression, and one from washing a biopsy needle. Whole genome analysis of three biopsy-derived primary neurospheres revealed that these samples shared genomic alterations when compared to the primary tumors. All cell lines retained major oncogenic driver mutations in genes such as , , and The needle-wash derived cell line was immortalized with hTERT, and exhibited the most deviation in mutation profiles and copy number alterations compared to primary tumor. Global DNA methylation profiling of seven primary tumor biopsies and matched primary neurospheres revealed similar epigenetic profiles. Primary neurospheres derived from biopsies were treated with the same specialized panel of agents recommended by a personalized medicine tumor board, which was based on the mutational profiles of the original tumor. SIGNIFICANCE: All cell lines exhibited varying levels of sensitivity to single agent indicating patterns of intertumor heterogeneity. The use of these model systems allows testing of combinatorial precision therapy for patients with DIPG, where there is a need for rapid translation into clinical trials.
  • 6.

    【2hr】DIPG-35. OPEN DIPG INITIATIVE: A PLATFORM FOR ACCELERATING DISCOVERY THROUGH DATA ACCESS, CONSOLIDATION AND HARMONIZATION

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    机译 DIPG-35。开放式DIPG计划：通过数据访问，整合和协调来加速发现的平台
    摘要：Pediatric brain cancers remain amongst the most lethal childhood cancers with over five decades of failed clinical trials. However, precision based clinical trials incorporating upfront biopsies, postmortem biobanking, along with technological advancements have resulted in a remarkable surge of omics and molecular based tumor classifications as well as a fundamental revision of WHO grading of pediatric brain tumors. However clinical translation of such molecular advancements has yet to impact a broad range of pediatric brain cancers. Major factors contributing to this lag of translation include, data fragmentation across institution, lack of data harmonization, data access, computational limitation, and the paucity of linked clinical and molecular data. To address these obstacles, we set to develop a unique data sharing platform for diffuse intrinsic pontine glioma (DIPG); one of the most devastating childhood brain caners. This initiative, named Project Open DIPG (POP DIPG) intends to consolidate and harmonize DIPG omics across all exiting and newly developed molecular data. Here we report that an international collaboration lead by Children’s Brain Tumor Tissue Consortium (CBTTC) has successfully launched POP DIPG housing the largest OMICs resource for DIPG and midline gliomas to date. Specifically POP DIPG houses the following molecular data: whole genome, whole exome, transcriptome, proteome, methylome of 850 unique subjects, over 1000 specimens and 20 avatar models of the disease. Harmonized and analyzed data are available through PedCBioportal providing the ease of access, rapid queries and hypothesis driven inquiries. Access to raw files is also granted though CBTTC to investigators with defined projects and hypotheses. With the expansion of POP DIPG, preclinical drug testing will be incorporated to accelerate discovery and more importantly to facilitate molecular-driven precision clinical trials. Open DIPG initiative will serve as a model for other challenging childhood cancers by bridging the current gap in bench to bedside translation.
  • 7.

    【2hr】DIPG-33. HARMONIZATION AND CHARACTERIZATION OF POSTMORTEM DONATIONS FOR PEDIATRIC BRAIN TUMORS

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    机译 DIPG-33。小儿脑肿瘤的点滴捐赠的协调和表征
    摘要：RATIONALE: A major factor contributing to the expanding knowledge of CNS tumors, specifically DMG biology is the selfless gift from patients and their families of postmortem tumor tissue. To facilitate this, we developed a postmortem donation program for collection of tissue and biospecimens for accelerating biology studies of end stage disease for pediatric CNS tumors. METHODS: Our postmortem program entails coordinating tissue donations, compiling clinical data, processing of whole brain, spinal cord, biofluids, and germline controls. Through our protocol, primary and disseminated tumor specimens are designated for molecular characterization and for generation of a matched preclinical model. RESULTS: During the past eight years, we coordinated and accrued over 50 autopsy cases including diffuse midline gliomas, ATRT, ETANTR, CPC from 20 institutions across North America and the United Kingdom. We report that approaching a family at the time of progression has provided the most successful outcome for consent to our program. Patient age range was from 11months to 20 years old. The median time from postmortem donation to tissue processing range was 13 hours with the earliest time point being 4 hours and the longest being 96 hours. All collected specimens were successfully processed and assessed for DNA/RNA integrity using bioanalyzer, attempted primary neurosphere cultures and cryopreserved for future molecular studies. PDX generation from fresh tissue proved more successful compared to primary neurospheres and post mortem time did not seem to have an effect. We have successfully generated models that represent molecular subgroups of DMGs such as H3.3/ H3.1- K27M and H3 WT. All generated preclinical models were validated by STR analysis and immunohistochemical assays using human mitochondrial antibodies. IMPACT: Postmortem tissue donations serve as an invaluable source for access to end-stage disease biology, generation of PDX models, studying patterns of tumor migration, testing combination therapy and preclinical drug testing.
  • 8.

    【2hr】EPEN-01. CHARACTERIZATION AND DRUG TESTING IN PRECLINICAL EPENDYMOMA MODELS

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    机译 EPEN-01。临床上室管膜模型的表征和药物测试
    摘要：INTRODUCTION: Currently there are no effective chemotherapeutic treatments for ependymomas, with maximal surgical excision and radiotherapy the mainstays of treatment. The identification of at least 9 molecularly distinct subgroups, suggests effective treatments are likely to be subgroup specific and subgroup focused preclinical investigations are urgently needed. However, such investigations have been hampered by the lack of appropriate and models in which to test potential treatments. This study aims to establish such models for the purpose of testing novel subgroup specific drug treatments. METHODS/RESULTS: Ependymoma samples from two patients have been successfully cultured in neurobasal media, with the cells growing both as adherent cultures and neurospheres. Whole genome DNA methylation screening and IHC, categorized the samples as falling within the ST-RELA and PFA subgroups respectively. Drug testing on ST-RELA neurospheres has shown treatment with Bortezomib, in combination with either Vorinostat or Panobinostat, results in significant synergistic benefits, with neurosphere viability reduced to almost zero, using doses that are half the IC50 of each drug. Preliminary analysis suggests the drugs are leading to an increase in apoptosis. Brain slice co-culture models have been successfully established, for the purpose of further drug testing and investigating the effects of the drugs upon normal brain tissue. Cells dissociated from the ST-RELA patient sample and low passage cultures, injected intracranially into NSG mice, resulted in tumour formation in 6 of the 19 mice, with plans underway to test the drug combinations in PDX mouse models. CONCLUSION: In the absence of known driver mutations for 8 of the 9 ependymoma subgroups, the establishment of patient derived preclinical models provides a mechanism for testing novel subgroup specific treatments. The current results suggest that Bortezomib in combination with histone deacetylase inhibitors may be an effective treatment in patients with ST-RELA ependymomas.
  • 9.

    【2hr】EPEN-02. MULTIPLATFORM MOLECULAR PROFILING REVEALS INTRATUMOR HETEROGENEITY IN EPENDYMOMA

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    机译 EPEN-02。室管膜瘤的多平台分子分析揭示了瘤内异质性
    摘要：OBJECTIVES: Ependymomas are associated with distinct anatomic, genomic and clinical characteristics, but the diversity of molecular features within individual ependymomas is unknown. Here, we perform multiplatform molecular profiling of 6 spatially- and radiographically-distinct regions of an ependymoma with fusion to elucidate intratumor heterogeneity. METHODS: Immunohistochemistry, whole exome sequencing, 850k DNA-methylation profiling, RNA-seq, and quantitative MRI were performed to define the genomic and radiographic characteristics of stereotactically-collected regions of an ependymoma. Molecular phylogenetic analysis was performed using methylation- and DNA-based variants, and functional assays were conducted in cell culture. RESULTS: All ependymoma regions were diffusely positive for L1CAM and contained the pathogenic fusion, but not fusion, along with chromosome 11 chromothripsis. Principal component analysis of transcriptomic data identified three molecularly distinct regions corresponding to stem cell/proliferation ( ), neuronal differentiation ( , ), and immune/stress response ( , ), each of which reflected transcriptional programs of distinct cell types in neural development. Furthermore, transcriptional heterogeneity correlated with differences in blood perfusion quantified by MRI. Phylogenetic analysis of methylation-derived CNVs and whole exome-derived SNVs revealed early chromosomal structural alterations followed by point mutations that distinguish various regions. A novel mutation in was discovered in all regions, and overexpression of this novel mutant ( ) led to increased cell proliferation and viability, suggesting that epigenetic misregulation could be a driver of ependymoma heterogeneity. CONCLUSION: Anaplastic ependymoma is associated with a previously unappreciated molecular heterogeneity that may influence tumorigenesis and design of molecular therapeutics.
  • 10.

    【2hr】DIPG-37. THE KETONE BODY β-HYDROXYBUTYRATE ACTS AS AN EPIGENETIC MODIFIER AND INCREASES RADIATION-INDUCED DNA DAMAGE IN DIFFUSE INTRINSIC PONTINE GLIOMA

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    机译 DIPG-37。酮体β-羟基丁酸酯作为表观修饰剂，并增加弥散性内源性胶质胶质瘤中辐射诱导的DNA损伤
    摘要：Diffuse Intrinsic Pontine Glioma (DIPG) is a highly infiltrative pediatric tumor with a median survival of approximately 9 months. Due to its location, the tumor is generally considered inoperable and there are few therapeutic options. Radiation is the only primary treatment for these tumors; however, this provides only short-term benefits. New therapeutic modalities are critically needed, and recent publications have suggested that a more effective treatment regime may involve multiple concurrent therapies that also potentiate radiation. A variety of combination treatments are under investigation, particularly those including histone deacetylase inhibitors (HDACi). Unfortunately, the use of multiple pharmaceutical agents often leads to unacceptable toxicity and side effects. One potential non-toxic therapy is metabolic ketosis which can be achieved using a therapeutic ketogenic diet (KD). The KD causes an increase in blood ketones and a decrease in blood glucose and has been used to safely treat refractory pediatric epilepsy. We have previously used human and murine high-grade glioma cells and a mouse model of high grade glioma to demonstrate that therapeutic ketosis has pluripotent anti-tumor activity alone and in combination with radiation. BHB has been shown to act as an endogenous HDACi. As such, the potential therapeutic underpinnings of the KD may involve the epigenetic-modifying capabilities of BHB. We now report that BHB causes significant growth inhibition in a DIPG cell line (SU-DIPG33; a generous gift from M. Monje, Stanford U.). In addition, BHB increases radiation induced DNA damage as measured by γH2AX western blot analysis. These data suggest that therapeutic ketosis may be a non-toxic adjuvant therapy that both potentiates radiation and inhibits the growth of DIPG cells. (supported by Students Supporting Brain Tumor Research and the Jaydie Lynn King Program in Neuro-oncology).
  • 11.

    【2hr】DIPG-38. DIANHYDROGALACTITOL (VAL-083) WITH AZD1775 INCREASES SURVIVAL IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG), IN VIVO

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    机译 DIPG-38。带有AZD1775的双氢半乳果酚（VAL-083）可增加体内弥漫性内源性胶质胶质瘤（DIPG）的存活率
    摘要：VAL-083 is a bi-functional DNA-targeting agent that crosses the blood-brain barrier and accumulates in brain tumors. VAL-083 induces interstrand crosslinks leading to DNA double-strand breaks and S/G2 cell-cycle arrest. We hypothesized that by inhibiting G2 checkpoint regulator kinase Wee1, cancer cells with VAL-083 induced DNA damage would progress past the G2 checkpoint leading to premature mitosis and cancer cell death. Herein we assess the activity of VAL-083 as well as in combination with the Wee1 inhibitor AZD1775 in patient-derived model systems of DIPG. DIPG derived cell-lines SF8628 and NEM157 (H3.3K27) were treated with increasing concentrations of single agent VAL-083 and in combination with AZD1775. To determine synergistic activity, we calculated the combination index (CI) using the Chou-Talalay method. activity of VAL-083 (3 mg/kg) as single agent or in combination with AZD1775 (60 mg/kg) was assessed in an orthotopic engraftment model of DIPG (SF8628). The IC of single agent VAL-083 ranged from 1µM to 10µM. The combination of VAL-083 and AZD 1775 exhibited synergistic activity in SF8628 and NEM157 with CI values ranging from 0.4 to 0.95 (CI<1 indicating synergy). , single-agent VAL-083 and in combination with AZD1775 conferred significant survival benefit compared to both untreated control and single-agent AZD1775. The median survival for mice treated with VAL-083 alone was 54.5 days vs. control (44 days, p=0.0004) and the combination was 62 days vs. control (44 days, p<0.0001) or mice treated with single-agent AZD1775 (47 days, p=0.0839). Our results suggest that VAL-083 in combination with a Wee1 inhibitor such as AZD1775 might offer a promising new therapeutic strategy for children with DIPG. Ongoing studies assessing the activity in other DIPG models as well as exploring the underlying mechanism-of-action of the combination strategy will be reported.
  • 12.

    【2hr】EPEN-07. EPENDYMOMAS IN INFANCY: UNDERLYING GENETIC ALTERATIONS, HISTOLOGICAL FEATURES AND CLINICAL OUTCOME

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    机译 EPEN-07。婴儿期的表皮瘤：遗传改变，组织学特征和临床结果
    摘要：Young age represents an adverse prognostic factor in children with ependymomas. Their treatment is challenging since beneficial therapeutic options are limited. As ependymomas are considered a biologically heterogeneous group we aimed to characterize infant ependymomas in respect to their histological and genetic features. We analyzed 28 ependymomas in children younger than 18 months at diagnosis treated according to HIT2000-E protocols in which irradiation was postponed until the age of 18 months. All cases underwent neuropathological review, including immunohistochemical characterization. Genome-wide copy number alterations (CNA) were assessed by molecular inversion probe assays and and fusions were detected by RT-PCR and sequencing. All infant ependymomas were anaplastic (WHO grade III). Complete resection was accomplished in 57% of cases. 75% of cases were located in the posterior fossa, all of which showing loss of H3-K27me3, characteristic for PFA ependymomas. CNA analysis showed a stable genome in all cases. No gain of chromosome 1q was observed, an adverse prognostic marker in PFA tumors of older children. After a median follow-up of 5.4 years, 71% relapsed, and 43 % died. Seven ependymomas occurred in the supratentorial region of which in only two cases a complete resection could be achieved. Four tumors carried fusions and two cases typical fusions (one case, not analyzable). The -fused cases did not display loss as an adverse indicator of prognosis in this disease entity. Although 43% of infants with supratentorial ependymomas relapsed, all patients survived (median follow-up, 8.0 years). Infant ependymomas seem to consist of three biological entities: supratentorial tumors carrying or fusions and PFA ependymomas. The latter showed a particularly unfavorable outcome even though chromosome 1q gain was not present. Further biological studies are warranted in these neoplasms to identify prognostic markers and suitable targets for a more effective treatment.
  • 13.

    【2hr】EPEN-04. CXorf67 MIMICS ONCOGENIC HISTONE H3 K27M MUTATIONS AND FUNCTIONS AS INTRINSIC INHIBITOR OF PRC2 FUNCTION IN AGGRESSIVE POSTERIOR FOSSA EPENDYMOMA

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    机译 EPEN-04。 CXorf67 MIMICS癌基因组蛋白H3 K27M的突变和功能作为大面积后房脓毒症中PRC2功能的内源性抑制剂
    摘要：Posterior fossa A (PFA) ependymomas comprise one out of nine molecular groups of ependymoma. PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark. Recently, we reported overexpression of as hallmark of PFA ependymoma and that CXorf67 can interact with polycomb repressive complex 2 (PRC2) thereby inhibiting EZH2. However, a detailed description of the functional domains of CXorf67 and the exact mechanism of EZH2 inhibition is still lacking. We now have performed mass spectrometry (MS) analyses of different CXorf67 protein truncates to identify functional domains in the CXorf67 protein involved in the binding of PRC2 core components. Our results show that PRC2 components like EZH2 and SUZ12 specifically bind to the C-terminal part of the CXorf67 protein. Overexpression of this C-terminal part of CXorf67 was sufficient to induce a strong downregulation of H3K27me3 in HEK293 cell lines. Upon inspection of the amino acid sequence in the C-terminus we discovered that a small, highly conserved amino acid sequence is responsible for binding and inhibition of EZH2 resulting in the perturbation of PRC2 function. A synthetic 21 amino acids long peptide containing these conserved amino acids completely abolished PRC2 activity in a methyltransferase assay. Strikingly, analyses showed that the CXorf67 peptide mimics the H3K27M peptide and both can bind to the SET domain of EZH2, suggesting that the mechanism of EZH2 inhibition by CXorf67 was highly similar to the mechanism observed in pediatric high-grade gliomas harboring H3K27M mutations. Taken together, our findings shed light on the functional domains of CXorf67 and reveal a crucial oncogenic mechanism that may be exploited for targeted therapy in PFA ependymoma.
  • 14.

    【2hr】EPEN-08. PHARMACOGENOMICS REVEALS ERBB2 AS A THERAPEUTIC TARGET IN PRIMARY EPENDYMOMA CULTURES

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    机译 EPEN-08。药物基因组学揭示ERBB2作为原发性表皮瘤培养的治疗靶标
    摘要：Ependymoma represents the third most common brain tumor entity of childhood. Successful targeted treatment approaches especially for RELA fusion-positive supratentorial ependymomas and posterior fossa type A ependymomas, the two subgroups known to be associated with worst prognosis, have so far not been discovered. We set up a high-throughput drug screening (HTS) pipeline to evaluate therapeutic efficacy of established chemotherapeutic agents and novel anti-cancer compounds currently in phase III and IV studies (n=196) in primary ependymoma cultures (n=12). Assay miniaturization to 1536-well microplates emerged as a key feature to enable drug screening from smallest sample amounts. Primary cultures faithfully recapitulated DNA methylation changes and copy number profiles detected in the corresponding primary tumors. In addition, entity and subgroup affiliation were consistent using molecular neuropathology 2.0 based classification (MNP 2.0, Capper, D. et al., Nature, 2018). These results confirm that the (epi)genetic landscape is maintained in short-term primary ependymoma cultures. We revealed remarkable chemoresistance by comparing HTS data of ependymomas to other established pediatric brain tumor models (n=48) and normal tissue controls (n=3). Notably, we identified Neratinib, an irreversible ERBB2 inhibitor, as the most prominent candidate drug amongst multiple targeted therapeutics with its preferential antitumoral activity in a subset of ependymoma cases (n=5). To unravel the mechanism of action of Neratinib, RNA sequencing of treated and untreated ependymoma cell lines (n=3) was conducted demonstrating highly specific abrogation of ERBB2 signaling. In summary, our study demonstrates the feasibility of primary culture drug screening for pediatric brain tumors to identify novel therapeutic approaches. Specifically, we identified preferential antitumoral activity of Neratinib in ependymomas providing a novel therapeutic approach for a largely chemoresistant entity.
  • 15.

    【2hr】EPEN-06. YAP1 SUBGROUP SUPRATENTORIAL EPENDYMOMA REQUIRES TEAD AND NUCLEAR FACTOR I-MEDIATED TRANSCRIPTIONAL PROGRAMS FOR TUMORIGENESIS

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    机译 EPEN-06。 YAP1亚群室膜上皮增生症需要茶和核因子I介导的透皮转录程序
    摘要：Ependymoma (EPN) is one of the most aggressive pediatric brain tumors, often arising in the supratentorial (ST) region. Our previous DNA methylation profiling study has identified ST-EPN subgroups that are characterized by YAP1-related fusions through genomic structural rearrangements (hereafter called as ST-EPN-YAP1). No reports of amplification and hyper-activation of the gene in ST-EPN-YAP1s postulate that YAP1-related fusions could have unique oncogenic function(s) in this type of cancer. Nevertheless, the lack of adequate models for ST-EPN-YAP1 had hindered the discovery of YAP1-fusion-specific molecular mechanisms in EPN tumorigenesis and the development of effective targeted therapies for these tumors. Most recently, we developed a murine ST-EPN-YAP1 model by forced expression of YAP1-MAMLD1, the most dominant type of the fusion proteins in ST-EPN-YAP1 into cortical progenitors using in utero electroporation. Detailed histological analysis suggest that tumors arose from Pax6-positive neural stem cells, which is highly consistent with the highest expression of PAX6 in human ST-EPN-YAP1s across all EPN subgroups. MAMLD1-driven nuclear localization of the fusion protein is strongly associated with tumorigenesis. To investigate oncogenic functions of YAP1-MAMLD1, we performed a ChIP-seq analysis on human ST-EPN-YAP1 primary tumors with an anti-YAP1 antibody. Intriguingly, ST-EPN-YAP1-specific enhancers enriched for YAP1 peaks exhibited abundant transcriptional factor binding motifs of nuclear factor I and TEADs. Co-immunoprecipitation revealed that both TEAD and NFIA/B interact with YAP1-MAMLD1. Both the mutation of the TEAD binding site in the YAP1 fusion and dominant-negative inhibition of NFI proteins prevented tumor induction in mice. Collectively, we demonstrated that YAP1-MAMLD1 function as an oncogenic driver in ST-EPN-YAP1s through recruitment of TEAD and NFI transcriptional factors.
  • 16.

    【2hr】EPEN-10. 5-FU ENHANCES RADIATION THERAPY IN IN VITRO AND IN VIVO TREATMENT OF 1q+ PFA EPENDYMOMA

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    机译 EPEN-10。 5-FU增强1q + PFA表皮瘤的体外和体内放射治疗
    摘要：BACKGROUND: Chemotherapy trials in relapsed pediatric ependymoma trials have failed to show reproducible benefit. High-risk 1q+PFA ependymoma show have a particularly bad outcome, with radiation and surgery showing no benefit at relapse. Using two 1q+PFA1 cell lines, we identified several ependymoma specific FDA-approved oncology drugs, including fluorouracil (5-FU). The goal of our study was to determine the effect of combining 5-FU and radiation in in-vitro and in-vivo 1q+PFA models. METHODS: MAF-811 and MAF-928 cell lines along with our newly established orthotopic xenografts MAF-811_XC and MAF-928_XC were used to measure treatment effects. Cesium radiation was used to treat cell lines and focal radiation was delivered to mice using 2Gy for 5 days. 30mg/kg 5-FU was dosed in mice once prior to radiation, once during, and weekly following radiation treatment for a total of 6 rounds of 5-FU. RESULTS: In-vitro studies, treating both 1q+PFA1 cell lines with escalating doses of 5-FU and radiation, we found synergistic effect on tritiated thymidine incorporation 7 days post radiation treatment. This effect was independent on sequence of drug and radiation dosage. In-vivo studies are ongoing with combining 10Gy focal radiation with 5-FU in both 1q+PFA xenografts. Preliminary studies have shown combination treatment appears to be well tolerated with 5-FU dosing. CONCLUSION: 5-FU treatment enhances the effect of radiation therapy in 1q+PFA models. Furthermore, these studies are the first to use both in-vitro and in-vivo models as rationale for developing clinical trials for this high-risk patient populations. An upfront clinical trial in 1q+PFA patients has been purposed.
  • 17.

    【2hr】EPEN-11. PROTEASOME AND HDAC INHIBITORS ARE CYTOTOXIC AGAINST RELA-FUSION PEDIATRIC EPENDYMOMA CELLS

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    机译 EPEN-11。蛋白质和HDAC抑制剂对Re-融合小儿室膜炎细胞具有细胞毒作用
    摘要：Ependymomas are the third most common pediatric brain tumor. Nine ependymoma subgroups have been described based on tumor location and genetics. Of supratentorial ependymomas, the C11orf95- fusion (ST-EPN-RELA) subgroup is the most aggressive. The encoded protein is an NF-κB transcription factor family member and activates NF-κB signaling. It has been reported that NF-κB and other pathways are important for ST-EPN-RELA tumors. We therefore hypothesized that ST-EPN-RELA cells may be sensitive to NF-κB signaling cascade inhibitors. To test our hypothesis we evaluated the cytotoxicity of multiple NF-kB signaling inhibitors on DKFZ-EP1NS RELA-fusion positive ependymoma cells and on our established patient-derived ST-EPN-RELA line (CPITT-1). Cells were treated with a single drug or combinations of drugs at concentrations ranging from 10 µM- 0.01 nM for 3–4 days and a WST-1 assay was used to assess viability. Of multiple inhibitors initially tested, Trichostatin A, a histone deacetylase (HDAC) inhibitor, in combination with MG-132, a proteasome inhibitor, displayed the highest level of cytotocity against both RELA-fusion lines. These findings led us to test clinically applicable drugs, including Marizomib, a brain penetrant proteasome inhibitor, and HDAC inhibitors, Panobinostat and Valproic acid. For DKFZ-EP1NS cells, the IC for Marizomib alone was 40.82 nM, Marizomib in combination with Panobinostat had an IC of 7.4 nM, and Marizomib in combination with Valproic Acid had an IC of 44.19. For CPITT-1 cells, the IC for Marizomib alone was 25.8nM, Marizomib in combination with Panobinostat had and IC of 3.07 nM, and Marizomib in combination with Valproic Acid had an IC of 27.04 nM. Overall, we observed that combination of proteasome and HDAC inhibitors are highly toxic to the RELA-fusion ependymoma cells tested. Further studies are warranted to evaluate the use these inhibitors for treating ST-EPN-RELA tumors.
  • 18.

    【2hr】EPEN-12. A COMMON FETAL DEVELOPMENTAL ORIGIN FOR PFA EPENDYMOMA, PFB EPENDYMOMA, AND CEREBELLAR PILOCYTIC ASTROCYTOMAS

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    机译 EPEN-12。 PFA表皮瘤，PFB表皮瘤和小脑上皮星形胶质细胞瘤的共同胎儿发育起源
    摘要：Single cell RNA-sequencing (scRNAseq) of the murine cerebellum at nine fetal and immediate post-natal (E10-P14) times points on >60,000 individual cells to identified >30 transcriptionally distinct cell clusters. Based on marker gene expression, many clusters resemble known cerebellar stem, progenitor, and differentiated cell types, while other clusters are more novel. Pseudo-time trajectory assisted in the reconstruction of known and novel developmental lineages, including the lineage of the cerebellar radial glia. A population of stem cells in the ventricular zone (VZ) gives rise to the progenitors of the GABAergic cerebellar interneurons, as well as the gliogenic progenitor cells, which subsequently become Bergmann glia and astrocytes. A novel, but clearly distinct and robust cluster of cells with transcriptional similarity to both the roof plate and the rhombic lip was identified. Comparison of bulk RNA-seq from human PFA, PFB, and cerebellar pilocytic astrocytomas (C-PA) reveals that all three-tumor types best transcriptionally match the gliogenic progenitor cells, with some similarity to VZ progenitor cells and ‘roof plate like’ stem cells. Furthermore, PFA and PFB temporally match to the gliogenic progenitors at E16, while C-PA resemble the E16-E18 the progenitor population. Subclustering of gliogenic progenitors reveals significant intra-cluster heterogeneity, with the ependymomas transcriptionally matching one subcluster, and the C-PA clearly matching a very different subcluster. scRNAseq of human PFA and C-PA reveals multiple tumor cell clusters within a given human ependymoma, with some clusters matching most closely to the gliogenic progenitors, and others matching best to the ‘roof plate like’ stem cells. Similarity to the ‘roof plate stem cells’ (E10-E14), and gliogenic progenitors (E14-E18) suggests an embryonic origin for PFA, PFB, and C-PA, suggests specific novel cells of origin, and offers a novel opportunity to understand posterior fossa tumor transcriptomic targets for novel therapy.
  • 19.

    【2hr】EPEN-09. PRECLINICAL MODELS REVEAL SUBGROUP-STRATIFIED TARGETED THERAPY OPTIONS FOR CHILDHOOD SUPRATENTORIAL EPENDYMOMA

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    机译 EPEN-09。临床前模型揭示亚组分层儿童靶向性室管膜瘤的靶向治疗选择
    摘要：Treatment of ependymoma has changed little over the years and is essentially limited to surgery and radiation. Limited preclinical testing has hindered the development of targeted therapies. Our group has identified a variety of potential therapy options for ependymoma based on drug screening using novel human posterior fossa ependymoma cell lines with chromosome 1q gain. Whether these agents were also effective in RELA fusion-driven supratentorial ependymoma was not determined due to of a lack of available supratentorial ependymoma cell lines. Recently we were able to generate a novel supratentorial cell line – MAF1329 - harboring 1q+ as well as the RELA-C11orf95 fusion. Paired with a supratentorial ependymoma cell line (EP1NS) obtained from collaborators, we were able to perform an screen and to identify supratentorial ependymoma-selective therapies in a panel of 124 FDA-approved oncology drugs, for streamlined clinical application. Additionally, we are able to compare drug sensitivities between supratentorial and posterior fossa ependymoma. Our initial findings indicate that the two ependymoma subgroups differ in response to therapy options with some overlap, notably RTKIs imatinib and pazopanib. We also noted that carmofur, a lypophilic-masked analog of 5-FU, was effective in treating both subgroups. Conversely, 5-FU itself, a top hit in posterior fossa ependymoma, showed very little effect in supratentorial models. Early phase trials of 5-FU resulted in a lack of survival benefit in supratentorial tumors enrolled in the study, and this preclinical finding may explain this lack of response. These data suggest that supratentorial and posterior fossa ependymoma may require subgroup specific targeted therapy options. Further comparative drug screening of other supratentorial cell lines and short term cultures, combined with testing, will address the need for subgroup-stratified preclinical data to better inform design of clinical trials in ependymoma.
  • 20.

    【2hr】EPEN-13. OUTCOMES AFTER FIRST RELAPSE OF CHILDHOOD INTRACRANIAL EPENDYMOMA: A SINGLE INSTITUTION EXPERIENCE

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    机译 EPEN-13。儿童首次颅内膜炎的缓解后的结果：单一机构的经验
    摘要：INTRODUCTION: Ependymoma is the third commonest malignant CNS tumor in children. Despite multimodal therapy, prognosis of relapsed ependymoma remains poor with long-term progression-free survival (PFS) of approximately 30%. Approaches to treating relapsed ependymoma are extremely varied. Here, we describe our experience and clinical outcomes of children after first relapse of intracranial ependymoma. METHODS: We performed a retrospective, IRB approved, chart review of patients with recurrent intracranial ependymoma treated at Dana-Farber / Boston Children’s Cancer and Blood Disorder Center from 1990 to 2017. RESULTS: Thirty-four patients with relapsed intracranial ependymoma (12 ST, 21 PF, 1 metastatic) were identified. Median time-to-first-relapse was 13.7 months (range:2.0–53.8). Eight patients had metastatic disease at first relapse. Five-year PFS and overall survival (OS) after first relapse was 23.5% and 60.9%, respectively. Median PFS and OS were 12 months and 66 months. Treatments for first relapse included surgery, radiation and/or chemotherapy/biologic therapy. GTR and localized disease were associated with improved OS on univariate analysis, with GTR being an independent prognostic factor for PFS and OS on multivariate analysis (p=0.02 & 0.013, respectively). Median PFS and OS for patients with GTR was 1.5 and 13 years, respectively (versus 0.4 and 2.3 years for STR / no resection [p=0.023 & 0.001, respectively]). Eighteen patients received radiation at first relapse (14 focal radiation, 8 re-irradiation). Patients who were radiated/re-irradiated at relapse showed longer median PFS and OS, however, these did not meet statistical significance. Chemotherapeutic (n=16) and biologic agents (n=3) used in this cohort were heterogenous and did not significantly impact outcome. Median time-to-second-relapse was 10.2 months (range:2.0–124.8). CONCLUSION: Relapsed intracranial ependymoma has a poor prognosis and unrelenting chronic course despite multimodal therapy. GTR is associated with improved outcomes after first relapse and should be pursued when possible. Novel therapeutic strategies are needed for this disease.
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