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  • 1
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    OMIC-09. MAPPING THE HISTONE MUTATIONAL LANDSCAPE ACROSS ADULT AND PEDIATRIC CANCER GENOMES UNCOVERS NOVEL SOMATIC MUTATIONS IN PEDIATRIC HIGH-GRADE GLIOMAS
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i39-i39
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i39-i39
    Abstract: There is a growing role for mutations affecting histone linker and histone core-encoding genes across several adult and pediatric cancers. However, the extent to which somatic histone mutations may bridge across different cancers as common tumorigenic events – particularly in the context of pediatric CNS tumors – remains unclear. To address this knowledge gap, we set out to define a comprehensive pan-cancer landscape of somatic histone mutations. We first queried the ICGC PCAWG and TCGA Pan-Cancer Atlas representing & gt;12,500 adult and pediatric cancer patients. We found lymphomas to be most enriched for histone mutations (50–75%) and, in particular, for mutations in linker histones (HIST1H1B-E), yet also in specific core histone genes (eg, HIST2H2BE). Moreover, we observed a significant enrichment of histone mutations in adult high-grade vs low-grade gliomas (10% vs 6%, P & lt;0.05, n=922 patients). Interrogation of whole genome data from 800 pediatric CNS tumor genomes (PBTA/OpenDIPG), identified novel (non-H3K27/non-H3G34) somatic histone mutations in 5–10% of subjects, including pediatric high-grade gliomas (pHGGs) and diffuse midline gliomas (DMGs). We found an overlapping set of histone genes to be recurrently mutated in non-CNS cancers and pediatric CNS tumors alike (eg, HIST1H1B/C/E). Notably, the only pediatric primary CNS lymphoma patient also harbored a histone linker alteration (HIST1H1B), similar to adult non-CNS lymphoma patients. We validated novel somatic histone mutations in DMGs by Sanger sequencing. Ongoing studies include in vitro assessment of the impact of these mutations on cell proliferation, chromatin accessibility, histone spacing, and gene expression. In addition, we will further assess associations with clinical outcome, age, and tumor subtypes. Collectively, oncohistone vulnerabilities were identified and defined as histone gene families recurrently mutated across all cancer types. Our analyses of adult and pediatric cancer genomes have uncovered previously unknown mutations affecting histone linker and core proteins, which may play a yet-undefined role in tumor etiology.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.156
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 2
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    Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. 9 ( 2022-09-01), p. 1438-1451
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. 9 ( 2022-09-01), p. 1438-1451
    Abstract: Pediatric diffuse midline gliomas (DMGs) are incurable childhood cancers. The imipridone ONC201 has shown early clinical efficacy in a subset of DMGs. However, the anticancer mechanisms of ONC201 and its derivative ONC206 have not been fully described in DMGs. Methods DMG models including primary human in vitro (n = 18) and in vivo (murine and zebrafish) models, and patient (n = 20) frozen and FFPE specimens were used. Drug-target engagement was evaluated using in silico ChemPLP and in vitro thermal shift assay. Drug toxicity and neurotoxicity were assessed in zebrafish models. Seahorse XF Cell Mito Stress Test, MitoSOX and TMRM assays, and electron microscopy imaging were used to assess metabolic signatures. Cell lineage differentiation and drug-altered pathways were defined using bulk and single-cell RNA-seq. Results ONC201 and ONC206 reduce viability of DMG cells in nM concentrations and extend survival of DMG PDX models (ONC201: 117 days, P = .01; ONC206: 113 days, P = .001). ONC206 is 10X more potent than ONC201 in vitro and combination treatment was the most efficacious at prolonging survival in vivo (125 days, P = .02). Thermal shift assay confirmed that both drugs bind to ClpP, with ONC206 exhibiting a higher binding affinity as assessed by in silico ChemPLP. ClpP activation by both drugs results in impaired tumor cell metabolism, mitochondrial damage, ROS production, activation of integrative stress response (ISR), and apoptosis in vitro and in vivo. Strikingly, imipridone treatment triggered a lineage shift from a proliferative, oligodendrocyte precursor-like state to a mature, astrocyte-like state. Conclusion Targeting mitochondrial metabolism and ISR activation effectively impairs DMG tumorigenicity. These results supported the initiation of two pediatric clinical trials (NCT05009992, NCT04732065).
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac041
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 3
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    DIPG-03. IDENTIFICATION OF NEW THERAPEUTIC TARGETS BY ARRAYED CRISPRA-BASED APPROACH TO MAP RADIORESISTANCE IN DMG
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i13-i13
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i13-i13
    Abstract: Pediatric Diffuse Midline Glioma (DMG) is amongst the most aggressive childhood brain tumors. The dismal prognosis is less than a year for children diagnosed. Radiotherapy (RT) remains the only standard treatment that provides only transient relief of clinical symptoms of DMG patients. Poor survival is associated with radio-resistance due in part to P53 mutational status and to invasive tumor properties related to epigenetic dysregulation. Over 80% of DMG patients harbor oncohistone 3 mutations (H3K27M) leading to global genome hypomethylation and transcriptional disruption. Transcriptional factors are known as master regulators of the genome but their implication in response to radiation treatment remains unclear. We developed an arrayed-CRISPR screen strategy to understand the role of transcription factors in radioresistance mechanisms in DMG-patient-derived cells. We performed arrayed-CRISPRa screening in multiwell plates with DMG cells expressing the dCas9-VP64, infected with gRNA lentiviral library to target each transcription factor (one transcription factor overexpressed per well). Each plate was irradiated fractionally (2Gy/day) and after irradiation stopped a comparison between cells overexpressing one targeted transcription to internal controls (non-targeted-gRNA infected cells) has been conducted. Transcription factor “hits” identification is based on Log2FC (logarithm 2 fold-change) with a value higher than 0.6, considering these targets as potentially involved in DMG cell radio-resistance and/or proliferation mechanisms. We identified 82 “hits” with more than 30% described as involved in radio-resistance mechanisms and/or tumorigenesis process, sustaining our screen results. We focus on “hits” with a Log2FC higher than 1 to identify the most robust targets playing a role in resistance to radiation. Currently, DMG cells are being treated with RT combination with pharmacological inhibitors to validate our candidate target involvement in DMG radio-resistance. Our goal is to achieve a better understanding of resistance mechanisms to identify therapeutic treatments to combine with radiotherapy to overcome radio-resistance developed by DMG cells.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.050
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 4
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    DIPG-25. MAPPING TUMOR MICROENVIRONMENT USING EMERGING TECHNOLOGIES FOR PEDIATRIC BRAIN CANCERS
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i18-i18
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i18-i18
    Abstract: Diffuse midline glioma (DMG) is a fatal childhood brain cancer with a survival rate of less than one year from diagnosis. Pharmacological approaches as well as immunotherapy have failed to make a clinical impact. Incomplete understanding of the tumor microenvironment (TME) and tumor associated antigens have contributed to the observed poor prognosis. We hypothesize that characterization of the DMG TME will identify biology-informed targeted treatments. We thus obtained postmortem specimens from 70 patients diagnosed with brain cancers, including 50 DMGs, 20 other types and 10 non-CNS-cancer patients. Up to four anatomical brain locations were selected including the primary tumor, metastatic and adjacent healthy sites. Formalin-fixed-paraffin-embedded (FFPE) specimens were processed for constructing a tissue microarray (TMA). The TMA was stained for a number of markers (H & E, H3K27M, H3K27me3, KI67) and was scored by a neuropathologist. We then used a multiplexed immunofluorescence (MxIF) technology, Cell DIVE™, to iteratively probe 33 biomarkers on a single tissue slide, focusing on immune cell type profiling and activation, and histone mutation status. Analysis of biomarker density and spatial relationships are underway. The main expressed immune markers across all patients were CD163, CD68, and CD8. CD8, a cytotoxic T-cell biomarker, was highly detected in pons, cerebellum, thalamus and the frontal lobe (tumor and healthy) of DMG patients and varied according to clinical intervention, including ONC201 treatment. Furthermore, in comparison to other tumors, DMGs exhibited a higher expression of CD3, T- cell marker, and CD4, a T-helper cell biomarker. Analysis of Iba1, a microglial marker, confirmed a higher difference in microglial activation in primary tumor compared to metastatic and adjacent healthy tissue. In contrast, CD68 was significantly increased in metastatic sites. Analysis is still ongoing. We report establishment of the most comprehensive TMA for pediatric brain tumors, which provides insights into TME comparing critically important clinical variables.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.072
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 5
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    DIPG-23. THE ROLE OF FOXO3 IN DMG RESISTANCE AND RESPONSE TO THERAPIES TARGETING DMG METABOLISM
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i17-i18
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i17-i18
    Abstract: Pediatric diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), are the most difficult childhood brain cancers to treat, with an overall survival rate of less than 12 months from diagnosis. Despite the H3K27M mutation being the main tumor driver, activation of the PI3K/Akt pathway also occurs, altering cancer cell metabolism, increasing glycolysis, and proliferation. Our research aims to understand the underlying mechanisms of resistance to therapies targeting DMG metabolism and to develop more effective treatment strategies. We have studied the effectiveness of ONC201 in targeting DMG cancer metabolism through mitochondrial degradation, reactive oxygen species increase, and oxidative phosphorylation impairment. Our findings suggest that despite promising results in patients, DMG tumor cells switch to glycolysis after treatment through PI3K/Akt pathway activation, which contributes to chemoresistance. We have found that the FOXO3 transcription factor plays a crucial role in determining DMG tumor sensitivity to therapy, specifically in the response to combined ONC201 and PI3K inhibitors. We have shown that FOXO3 activity is abolished via PI3K pathway activation in resistant DMG cell lines, leading to cytoplasmic translocation and tumor cell survival. Additionally, we found that the expression of FOXO3 is dysregulated in DMG patient tumors. Our data implies that a failure of FOXO3 to reach the nucleus may be a contributing factor to the inadequate response seen in certain ONC201 treated DMG patients. By utilizing CRISPR-modified patient-derived DIPG cells in vitro, we investigated the impact of FOXO3 knockout/overexpression on tumor sensitivity to various treatment regimens. We have validated new PI3K inhibitors and FOXO3 activators as potential therapeutic strategies for DMG patients. Our findings suggest that targeting FOXO family of transcription factors may be a promising approach to improve the efficacy of metabolic-targeting therapies for DMGs and ultimately improve the survival of patients diagnosed with this challenging pediatric brain cancer.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.070
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 6
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    Real-Time Drug Testing of Pediatric Diffuse Midline Glioma to Support Clinical Decision Making: The Zurich DIPG/DMG Center Experience
    Elsevier BV ; 2022
    In:  SSRN Electronic Journal
    Details
    In: SSRN Electronic Journal, Elsevier BV
    Type of Medium: Online Resource
    ISSN: 1556-5068
    URL: Article
    DOI: 10.2139/ssrn.4180012
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 7
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    An in vitro osteosarcoma 3D microtissue model for drug development
    Elsevier BV ; 2014
    In:  Journal of Biotechnology Vol. 189 ( 2014-11), p. 129-135
    Details
    In: Journal of Biotechnology, Elsevier BV, Vol. 189 ( 2014-11), p. 129-135
    Type of Medium: Online Resource
    ISSN: 0168-1656
    URL: Article
    DOI: 10.1016/j.jbiotec.2014.09.005
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
    detail.hit.zdb_id: 2016476-2
    SSG: 12
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  • 8
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    DIPG-64. INTERNATIONAL PRECLINICAL DRUG DISCOVERY AND BIOMARKER PROGRAM INFORMING AN ADOPTIVE COMBINATORIAL TRIAL FOR DIFFUSE MIDLINE GLIOMAS
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii300-iii300
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii300-iii300
    Abstract: DMG-ACT (DMG- multi-arm Adaptive and Combinatorial Trial) aims to implement a highly innovative clinical trial design of combinatorial arms for patients with diffuse midline gliomas (DMGs) at all disease stages that is adaptive to pre-clinical data generated in eight collaborating institutions. The goals of the team are to: i) rapidly identify and validate promising drugs for clinical use, and ii) predict biomarkers for promising drugs. METHODS In vitro (n=15) and in vivo (n=8) models of DMGs across seven institutions were used to assess single and combination treatments with ONC201, ONC206, marizomib, panobinostat, Val-083, and TAK228. In vivo pharmacokinetic assays using clinically relevant dosing of ONC201, ONC206, and panobinostat were performed. Predictive biomarkers for ONC201 and ONC206 were identified using extensive molecular assays including CRISPR, RNAseq, ELISA, FACS, and IHC. RESULTS Inhibitory concentrations (IC50) were established and validated across participating sites. In vivo validation of single and combination drug assays confirmed drug efficacy as increased survival for: ONC201 (p=0.01), ONC206 (p=0.01), ONC201+ONC206 (p=0.02), and ONC201+panobinostat (p=0.01). Marizomib showed toxicity in murine/zebrafish PDXs models. Murine pharmacokinetic analysis showed peak brain levels of ONC201 and ONC206 above pre-clinical IC50. Molecular testing and analyses of existing drug screen across 537 cancer cell lines validated mitochondrial stress and ATF4 as the main targets induced by ONC201/6. CONCLUSION Thorough preclinical testing in a multi-site laboratory setting is feasible and identified ONC201 in combination with ONC206 as promising therapeutics for DMGs. Preclinical and correlative-clinical studies are ongoing.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.109
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 9
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    MODL-22. DEVELOPING A REAL-TIME PERSONALIZED DRUG TESTING PLATFORM FOR PEDIATRIC CNS CANCERS
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii415-iii415
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii415-iii415
    Abstract: The relatively small size of biopsied CNS tumors has presented a historical challenge for real-time drug screens. Moreover, in vivo assessment of drug response does not often benefit patients with aggressive gliomas given the relatively long time ( & gt;8 months) of tumor engraftment in the classic mouse PDX models. Here, we aimed to develop an innovative real-time in vivo and in vitro drug screening platform capable of analyzing a minimal number ( & lt;1E6) of cells obtained at biopsy. METHODS Existing primary cells were used to test 6 different culture platforms. The top platform was selected and used to expand tumor cells obtained of DMG biopsy. Tumor cells were validated using the minION sequencing platform. Single and combination drug (n=7) screens were performed. Effective drugs were further evaluated in zebrafish PDX and non-tumor bearing models to assess efficacy and toxicity, respectively. RESULTS A total of 8 biopsies were obtained. Successful cell expansion was achieved in 6/8 (75%) and a limited drug screen in 3/6 (50%) of cases. Single and combination drug (n=7) assays identified responder and non-responders to candidate drugs. Systemic toxicity of effective drugs was tested in non-tumor bearing zebrafish. Tumor cells were engrafted in zebrafish providing the opportunity for an in vivo screen. The entire process was completed within 21 days on average. CONCLUSIONS A novel platform was developed for rapid in vitro and in vivo drug screens of tumor cells obtained at biopsy. This platform will provide the opportunity to establish personalized therapy for heterogeneous cancers including DMGs.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.595
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 10
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    HGG-32. ONC201 AND ONC206 TARGET TUMOR CELL METABOLISM IN PEDIATRIC DIFFUSE MIDLINE GLIOMA PRECLINICAL MODELS
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i23-i24
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i23-i24
    Abstract: Diffuse midline gliomas (DMGs) remain incurable cancers and new treatments are urgently needed. One promising new therapeutic avenue for these cancers is targeting of metabolic vulnerabilities including a heightened dependence on mitochondrial metabolism. We and others have shown that the oral, brain-penetrant imipridone drugs ONC201 and ONC206 target mitochondrial metabolism in cancer cells. In particular, ONC201 and ONC206 hyper-activate the mitochondrial protease ClpP, impair mitochondrial oxidative phosphorylation (OXPHOS), activate the integrated stress response (ISR) signaling pathway, and induce apoptosis in DMG preclinical models. We validated ClpP as a key target of ONC206 by showing that CRISPR/Cas9-mediated CLPP knockout significantly decreased ONC206 sensitivity in DMG cells. We further showed that imipridone-mediated ClpP activation resulted in significant degradation of the chaperone protein ClpX. Moreover, ONC201 and ONC206 treatment inhibited mitochondrial respiration, decreased mitochondrial membrane potential and triggered extensive mitochondrial structural damage, including disintegration of mitochondrial cristae. Time-course RNA sequencing of five DMG cell lines treated with ONC201 and ONC206, alone or in combination, revealed robust ATF4 and CHOP upregulation, indicating potent activation of ISR signaling. Notably, ATF4/CHOP upregulation was strongest in ONC201/6 combination-treated cells, indicating synergy between the two drugs. We further explored drug combinations by testing ONC201 together with ONC206, Panobinostat, JQ1, and Osimertinib to identify synergistic combination treatments. The strongest synergistic effect was found over a broad IC50 range for ONC201 and ONC206. Finally, we showed that ONC201 and ONC206 significantly prolonged survival of mice bearing brainstem DIPG xenografts. Ongoing studies include assessment of the in vivo efficacy of ONC201 and ONC206 across different CNS tumor models, as well as investigation and validation of clinically relevant biomarkers of response to treatment. In summary, our preclinical data strongly support the utility of the mitochondrial targeting agents ONC201 and ONC206 for the treatment of DMG and other malignant brain tumors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.096
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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