382 results on '"Delaidelli, A."'
Search Results
102. Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma
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Ching C. Lau, Richard A. Moore, David Malkin, Poul H. Sorensen, Marco A. Marra, Ryan D. Morin, Gian Luca Negri, Timothy J. Triche, Bruno M. Grande, Alberto Delaidelli, Dawn R. Cochrane, Alexandre Montpetit, Amal El-Naggar, and Steven J.M. Jones
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Male ,0301 basic medicine ,DNA Copy Number Variations ,Gene Dosage ,Somatic hypermutation ,Bone Neoplasms ,Biology ,Polymorphism, Single Nucleotide ,Genome ,Article ,DNA sequencing ,Germline ,Pathology and Forensic Medicine ,Metastasis ,Genetic Heterogeneity ,03 medical and health sciences ,0302 clinical medicine ,Exome Sequencing ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,Exome sequencing ,Osteosarcoma ,British Columbia ,Whole Genome Sequencing ,Age Factors ,Gene Amplification ,Microsatellite instability ,medicine.disease ,United States ,3. Good health ,Phenotype ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Female ,Microsatellite Instability ,Neoplasm Recurrence, Local ,Transcriptome - Abstract
Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations. Sequencing of 13 osteosarcoma patients including 13 primary, 10 metastatic, and 3 locally recurring tumors revealed a highly heterogeneous mutational landscape, including cases of hypermutation and microsatellite instability positivity, but with virtually no recurrent alterations except for mutations involving the tumor suppressor genes RB1 and TP53. At the germline level, we detected alterations in multiple cancer related genes in the majority of the cohort, including those potentially disrupting DNA damage response pathways. Metastases retained only a minimal number of short variants from their corresponding primary tumors, while copy number alterations showed higher conservation. One recurrently amplified gene, KDR, was highly expressed in advanced cases and associated with poor prognosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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- 2019
103. CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors
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Siddhartha Mitra, Zhongyu Zhu, Anandani Nellan, Johanna Theruvath, Ezio Bonvini, Skyler P. Rietberg, Ravindra Majeti, Christopher Rota, Sabine Heitzeneder, Crystal L. Mackall, Elena Sotillo, Yongzhi Cui, Peng Xu, Alla Sekunova, Christopher Mount, Alberto Delaidelli, John M. Maris, Daniel W. Lee, Michelle Monje, Brad St. Croix, Robbie G. Majzner, Dimiter S. Dimitrov, Miles H. Linde, Poul H. Sorensen, Martha Quezado, Louai Labanieh, and Rimas J. Orentas
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0301 basic medicine ,Cancer Research ,B7 Antigens ,T-Lymphocytes ,medicine.medical_treatment ,Receptors, Antigen, T-Cell ,Immunotherapy, Adoptive ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,Medulloblastoma ,Receptors, Chimeric Antigen ,Brain Neoplasms ,business.industry ,Immunotherapy ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Pediatric cancer ,Chimeric antigen receptor ,Disease Models, Animal ,Treatment Outcome ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Osteosarcoma ,Sarcoma ,business - Abstract
Purpose: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system. Experimental Design: We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models. Results: B7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3. Conclusions: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.
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- 2019
104. IMMU-04. Transcriptional analysis reveals distinct microenvironmental subgroups across pediatric nervous system tumors
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Arash Nabbi, Pengbo Beck, Alberto Delaidelli, Derek A Oldridge, Sumedha Sudhaman, Kelsey Zhu, S Y Cindy Yang, David T Mulder, Jeffrey P Bruce, Joseph N Paulson, Pichai Raman, Yuankun Zhu, Martin Silll, Sebastian Brabetz, Sander Lambo, Pascal D Johann, Adam C Resnick, Poul H Sorensen, David Malkin, Marcel Kool, David T W Jones, Stefan M Pfister, Natalie Jäger, and Trevor J Pugh
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
INTRODUCTION: Recent clinical trials of immune checkpoint inhibitors indicated 5-11% response rate in pediatric patients depending on cancer type and expression of target proteins. Currently, a systematic analysis characterizing the immune microenvironment of childhood tumors is lacking. The main objective of this study is to uncover the features of immune microenvironment in pediatric nervous system tumors (pedNST). METHODS: We compiled transcriptomes of 925 tumors from three initiatives, Therapeutically Applicable Research To Generate Effective Treatments (TARGET, n = 149), International Cancer Genome Consortium (ICGC, n = 195) and Children Brain Tumor Tissue Network (CBTN, n = 581). We analyzed the performance of immune deconvolution tools and used publicly available datasets to define immune genesets. We conducted a consensus analysis to assign genes to cell-types and identify immunological groups. RESULTS: We found wide variability in immune infiltration across and within cancer types ranging from cold tumors such as medulloblastoma (2.7% infiltrate) to infiltrated entities such as neurofibroma (22.6%). Consensus clustering revealed four distinct immune clusters. The pediatric inflamed group (10%) included MYCN non-amplified neuroblastoma and ATRT. The myeloid-predominant group (30%) showed decreased infiltration of lymphoid cells but enrichment of myeloid cell genesets. The pediatric-cold group (42%) harbored no enrichment of immune genesets and included 72% of ependymomas and 65% of medulloblastomas. The immune excluded group (18%) showed depletion of immune cell-types and included sonic-hedgehog medulloblastoma. 71% of pedNST belonged to the lymphocyte depleted or immunologically quiet clusters, indicating the cold immune microenvironment in pedNST compared to adult cancers. CONCLUSION: We report characteristics of the immune microenvironment in pedNST. We found an overall cold microenvironment with low lymphocyte infiltration in this population compared to common adult cancers. We identified ~10% of tumors harboring a relatively inflamed microenvironment. Our data uncover characteristics of immune infiltration in pediatric tumors with potential implications to guide therapy.
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- 2022
105. Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication
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Heike E. Daldrup-Link, John Lattin, Menard M, Pons J, Peng Xu, Kristopher D. Marjon, Aidan Tousley, Louise Kiru, John L. Silberstein, Alberto Delaidelli, Payton L. Marshall, Nasholm N, William A. Weiss, Allison Banuelos, Amira A. Barkal, Poul H. Sorensen, Garry L. Coles, Irving L. Weissman, Sabine Heitzeneder, Benjamin A. H. Smith, Robbie G. Majzner, Ricardo A. Fernandes, Jonathan Huang, Julien Sage, Miles H. Linde, Shaurya Dhingra, Elena Sotillo, Johanna Theruvath, Rachel E. Brewer, Ravi Majeti, Cochran, Sangalang Er, Crystal L. Mackall, Dalton Gn, Wei Wu, Carolyn R. Bertozzi, Kuo Tc, and Andy He
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biology ,business.industry ,CD47 ,SIGLEC ,medicine.disease ,Blockade ,Neuroblastoma ,biology.protein ,Cancer research ,Macrophage ,Medicine ,Cytotoxic T cell ,Osteosarcoma ,Antibody ,business - Abstract
The disialoganglioside GD2 is consistently overexpressed in neuroblastoma and osteosarcoma, and is variably expressed in other sarcomas, gliomas, neuroendocrine tumors, and epithelial cancers. Anti-GD2 antibodies have improved the survival rates of patients with neuroblastoma only when administered as part of intense chemotherapy-based cytotoxic regimens, which are associated with debilitating late effects including hearing loss, growth retardation, and secondary leukemias. Despite broad expression of GD2 on osteosarcoma, anti-GD2 antibody has not mediated significant antitumor activity in that disease or any other GD2+ cancers. CD47 is a checkpoint molecule overexpressed on tumor cells that inhibits macrophage activity, and CD47 blockade has demonstrated promising clinical activity in early human trials. We investigated whether anti-CD47 antibody could enhance the efficacy of anti-GD2 antibody in neuroblastoma and other GD2+ malignancies. We demonstrate substantial synergy of these two agents, resulting in the recruitment of tumor associated macrophages (TAMs) to mediate robust and durable anti-tumor responses. The responses are driven by GD2-specific factors that reorient the balance of macrophage activity towards phagocytosis of tumor cells, including disruption of a newly described GD2:Siglec-7 axis. These results demonstrate the unique synergy of combining anti-GD2 with anti-CD47, which has the potential to significantly enhance outcomes for children with neuroblastoma and osteosarcoma and will soon be investigated in a first-in-human clinical trial.
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- 2021
106. EMBR-20. ELONGATION CONTROL OF MRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA
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Delaidelli, Alberto, primary, Negri, Gian Luca, additional, Wang, Que Xi, additional, Huang, Albert, additional, Sidhu, Simran, additional, Zhang, Joyce, additional, Huang, Yue Zhou, additional, Yao, Betty, additional, Langman, Sofya, additional, Vislovukh, Andrii, additional, Hovestadt, Volker, additional, Taylor, Michael, additional, Leprivier, Gabriel, additional, and Sorensen, Poul, additional
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- 2021
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107. EMBR-32. INTEGRATED STRESS RESPONSE PLAYS A PRO-SURVIVAL ROLE IN MYC-DRIVEN MEDULLOBLASTOMA
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Langman, Sofya, primary, Delaidelli, Alberto, additional, Huang, Yue Zhou, additional, and Sorensen, Poul, additional
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- 2021
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108. EMBR-21. CLINICALLY TRACTABLE OUTCOME PREDICTION OF GROUP 3/4 MEDULLOBLASTOMA BASED ON TPD52 IMMUNOHISTOCHEMISTRY: A MULTICOHORT STUDY
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Delaidelli, Alberto, primary, Dunham, Christopher, additional, Santi, Maria Rita, additional, Negri, Gian Luca, additional, Triscott, Joanna, additional, Zheludkova, Olga, additional, Golanov, Andrey, additional, Ryzhova, Marina, additional, Okonechnikov, Konstantin, additional, Schrimpf, Daniel, additional, Stichel, Damian, additional, von Deimling, Andreas, additional, Kool, Marcel, additional, Pfister, Stefan, additional, Ramaswamy, Vijay, additional, Korshunov, Andrey, additional, Taylor, Michael, additional, and Sorensen, Poul, additional
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- 2021
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109. Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma
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Zhang, Hai-Feng, primary, Hughes, Christopher S., additional, Li, Wei, additional, He, Jian-Zhong, additional, Surdez, Didier, additional, El-Naggar, Amal M., additional, Cheng, Hongwei, additional, Prudova, Anna, additional, Delaidelli, Alberto, additional, Negri, Gian Luca, additional, Li, Xiaojun, additional, Ørum-Madsen, Maj Sofie, additional, Lizardo, Michael M., additional, Oo, Htoo Zarni, additional, Colborne, Shane, additional, Shyp, Taras, additional, Scopim-Ribeiro, Renata, additional, Hammond, Colin A., additional, Dhez, Anne-Chloe, additional, Langman, Sofya, additional, Lim, Jonathan K.M., additional, Kung, Sonia H.Y., additional, Li, Amy, additional, Steino, Anne, additional, Daugaard, Mads, additional, Parker, Seth J., additional, Geltink, Ramon I. Klein, additional, Orentas, Rimas J., additional, Xu, Li-Yan, additional, Morin, Gregg B., additional, Delattre, Olivier, additional, Dimitrov, Dimiter S., additional, and Sorensen, Poul H., additional
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- 2021
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110. α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response
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Delaidelli, Alberto, primary, Richner, Mette, additional, Jiang, Lixiang, additional, van der Laan, Amelia, additional, Christiansen, Ida Bergholdt Jul, additional, Ferreira, Nelson, additional, Nyengaard, Jens R., additional, Vægter, Christian B., additional, Jensen, Poul H., additional, Mackenzie, Ian R., additional, Sorensen, Poul H., additional, and Jan, Asad, additional
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- 2021
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111. Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma
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Amy Li, Anna Prudova, Amal El-Naggar, Hongwei Cheng, Dimiter S. Dimitrov, Jian-Zhong He, Colin A. Hammond, Seth J. Parker, Rimas J. Orentas, Taras Shyp, Renata Scopim-Ribeiro, Xiaojun Li, Olivier Delattre, Christopher S. Hughes, Alberto Delaidelli, Mads Daugaard, Sonia H.Y. Kung, Htoo Zarni Oo, Jonathan K M Lim, Wei Li, Poul H. Sorensen, Hai-Feng Zhang, Anne-Chloe Dhez, Michael M. Lizardo, Shane Colborne, Anne Steino, Didier Surdez, Sofya Langman, Ramon I. Klein Geltink, Gregg B. Morin, Maj Sofie Ørum-Madsen, Li-Yan Xu, and Gian Luca Negri
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Adult ,Proteomics ,Cell ,Transsulfuration pathway ,Sarcoma, Ewing ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Humans ,Anoikis ,Child ,030304 developmental biology ,0303 health sciences ,Chemistry ,Cystathionine gamma-lyase ,Receptors, Interleukin-1 ,Glutathione ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Interleukin-1 Receptor Accessory Protein ,Cysteine - Abstract
Cancer cells must overcome anoikis (detachment-induced death) to successfully metastasize. Using proteomic screens, we found that distinct oncoproteins upregulate IL1 receptor accessory protein (IL1RAP) to suppress anoikis. IL1RAP is directly induced by oncogenic fusions of Ewing sarcoma, a highly metastatic childhood sarcoma. IL1RAP inactivation triggers anoikis and impedes metastatic dissemination of Ewing sarcoma cells. Mechanistically, IL1RAP binds the cell-surface system Xc− transporter to enhance exogenous cystine uptake, thereby replenishing cysteine and the glutathione antioxidant. Under cystine depletion, IL1RAP induces cystathionine gamma lyase (CTH) to activate the transsulfuration pathway for de novo cysteine synthesis. Therefore, IL1RAP maintains cyst(e)ine and glutathione pools, which are vital for redox homeostasis and anoikis resistance. IL1RAP is minimally expressed in pediatric and adult normal tissues, and human anti-IL1RAP antibodies induce potent antibody-dependent cellular cytotoxicity of Ewing sarcoma cells. Therefore, we define IL1RAP as a new cell-surface target in Ewing sarcoma, which is potentially exploitable for immunotherapy. Significance: Here, we identify cell-surface protein IL1RAP as a key driver of metastasis in Ewing sarcoma, a highly aggressive childhood sarcoma. Minimal expression in pediatric and adult normal tissues nominates IL1RAP as a promising target for immunotherapy. See related commentary by Yoon and DeNicola, p. 2679 . This article is highlighted in the In This Issue feature, p. 2659
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- 2020
112. GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity
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Sabine Heitzeneder, Kristopher R. Bosse, Zhongyu Zhu, Doncho Zhelev, Robbie G. Majzner, Molly T. Radosevich, Shaurya Dhingra, Elena Sotillo, Samantha Buongervino, Guillem Pascual-Pasto, Emily Garrigan, Peng Xu, Jing Huang, Benjamin Salzer, Alberto Delaidelli, Swetha Raman, Hong Cui, Benjamin Martinez, Scott J. Bornheimer, Bita Sahaf, Anya Alag, Irfete S. Fetahu, Martin Hasselblatt, Kevin R. Parker, Hima Anbunathan, Jennifer Hwang, Min Huang, Kathleen Sakamoto, Norman J. Lacayo, Dorota D. Klysz, Johanna Theruvath, José G. Vilches-Moure, Ansuman T. Satpathy, Howard Y. Chang, Manfred Lehner, Sabine Taschner-Mandl, Jean-Phillipe Julien, Poul H. Sorensen, Dimiter S. Dimitrov, John M. Maris, and Crystal L. Mackall
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Neuroblastoma ,Cancer Research ,Receptors, Chimeric Antigen ,Glypicans ,Oncology ,Cell Line, Tumor ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Animals ,Humans ,Immunotherapy ,Immunotherapy, Adoptive ,Xenograft Model Antitumor Assays - Abstract
Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets. We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density (∼5,000 molecules/cell, range 1-6 × 10
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- 2022
113. EMBR-32. INTEGRATED STRESS RESPONSE PLAYS A PRO-SURVIVAL ROLE IN MYC-DRIVEN MEDULLOBLASTOMA
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Yue Zhou Huang, Alberto Delaidelli, Poul H. Sorensen, and Sofya Langman
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Medulloblastoma ,Cancer Research ,Endoplasmic reticulum ,Biology ,medicine.disease ,Cell biology ,Fight-or-flight response ,Embryonal Tumors ,Oncology ,medicine ,Phosphorylation ,Integrated stress response ,AcademicSubjects/MED00300 ,Social role ,AcademicSubjects/MED00310 ,Neurology (clinical) ,Protein overexpression - Abstract
Medulloblastoma (MB) accounts for 20% of diagnosed brain tumors in children. Group 3 (G3) MB subtype is the most aggressive. Molecularly, G3 MB is characterized by MYC overexpression, which drives elevated mRNA translation in tumor cells. PERK is an eukaryotic translation initiation factor 2 (eIF2α) kinase that inhibits mRNA translation under endoplasmic reticulum (ER) stress conditions, such as in response to accumulation of unfolded proteins. When unfolded proteins accumulate in the ER, activated PERK phosphorylates eIF2α. This shuts down global translation and triggers integrated stress response (ISR) to help cells adapt through selective translation of mRNA encoding pro-survival proteins. High mRNA expression of PERK correlates with poor survival in G3 MB patients. In vitro, combination of ER or hypoxic stress with PERK knockdown induces apoptosis in MB cells. ISRIB is an ISR inhibitor that maintains translation rates despite eIF2α phosphorylation. Combining ISRIB with stress such as hypoxia induces apoptosis in MB cells and prevents accumulation of key ISR mediators such as ATF4. In addition, combination of ISRIB and hypoxia induces oxidative stress. Current G3 MB treatment regimens include vincristine, a known ISR inducer. Combination of ISRIB with vincristine amplifies vincristine-induced apoptosis, potentially suggesting novel therapeutic approach for MB. Our findings show that inhibition of ISR in G3 MB represents a powerful inducer of cancer cell death.
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- 2021
114. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma
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Carolina Nor, Martin Komosa, Olga Sirbu, Nabil Ahmed, Joonas Haapasalo, Kristen Fousek, Jonelle G. Pallota, Betty Luu, Cynthia Hawkins, Kenneth Aldape, Uri Tabori, David Przelicki, Srinidhi Varadharajan, Liam D. Hendrikse, Meenakshi Hegde, Claudia M. Kuzan-Fischer, Ana Guerreiro Stucklin, Tajana Douglas, Ahmed Z. Gad, Xiaochong Wu, Randy Van Ommeren, Polina Balin, Alex Manno, Sachin Kumar, Raul Suarez, Avesta Rastan, Craig Daniels, Mads Daugaard, Maria C. Vladoiu, Stephen Yip, Cory Richman, Michelle Ly, Matthew L. Baker, Kaitlin Kharas, Laura K. Donovan, Stephen C. Mack, Claudia C. Faria, Pasqualino De Antonellis, Ning Huang, Poul H. Sorensen, Zied Abdullaev, Lei Qin, Livia Garzia, Alyssa C. M. Joynt, A. Sorana Morrissy, Michael D. Taylor, Sujith K. Joseph, Antony Michealraj, Dilakshan Srikanthan, Florence M.G. Cavalli, Borja L. Holgado, John M. Maris, Alberto Delaidelli, Vijay Ramaswamy, Kevin Bielamowicz, Juliette Hukin, Donovan, L. K., Delaidelli, A., Joseph, S. K., Bielamowicz, K., Fousek, K., Holgado, B. L., Manno, A., Srikanthan, D., Gad, A. Z., Van Ommeren, R., Przelicki, D., Richman, C., Ramaswamy, V., Daniels, C., Pallota, J. G., Douglas, T., Joynt, A. C. M., Haapasalo, J., Nor, C., Vladoiu, M. C., Kuzan-Fischer, C. M., Garzia, L., Mack, S. C., Varadharajan, S., Baker, M. L., Hendrikse, L., Ly, M., Kharas, K., Balin, P., Wu, X., Qin, L., Huang, N., Stucklin, A. G., Morrissy, A. S., Cavalli, F. M. G., Luu, B., Suarez, R., De Antonellis, P., Michealraj, A., Rastan, A., Hegde, M., Komosa, M., Sirbu, O., Kumar, S. A., Abdullaev, Z., Faria, C. C., Yip, S., Hukin, J., Tabori, U., Hawkins, C., Aldape, K., Daugaard, M., Maris, J. M., Sorensen, P. H., Ahmed, N., and Taylor, M. D.
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0301 basic medicine ,Ependymoma ,Male ,medicine.medical_treatment ,T-Lymphocytes ,Immunotherapy, Adoptive ,Mice ,0302 clinical medicine ,Cerebrospinal fluid ,Drug Delivery Systems ,HEK293 Cell ,Cancer immunotherapy ,Tumor Cells, Cultured ,Neoplasm Metastasis ,Child ,Cerebrospinal Fluid ,Receptors, Chimeric Antigen ,Brain Neoplasms ,General Medicine ,Neoplasm Metastasi ,Treatment Outcome ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,Cancer Vaccine ,Human ,Cancer Vaccines ,General Biochemistry, Genetics and Molecular Biology ,Brain Neoplasm ,03 medical and health sciences ,medicine ,Animals ,Humans ,Cerebellar Neoplasms ,neoplasms ,Injections, Intraventricular ,Medulloblastoma ,Animal ,business.industry ,Cerebellar Neoplasm ,Infant ,Immunotherapy ,Recurrent Medulloblastoma ,medicine.disease ,Interleukin-13 receptor ,Xenograft Model Antitumor Assays ,Chimeric antigen receptor ,030104 developmental biology ,HEK293 Cells ,T-Lymphocyte ,Cancer research ,business ,Drug Delivery System - Abstract
Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood–brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.
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- 2019
115. Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication
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Theruvath, Johanna, primary, Menard, Marie, additional, Smith, Benjamin A.H., additional, Linde, Miles H., additional, Coles, Garry L., additional, Wu, Wei, additional, Kiru, Louise, additional, Delaidelli, Alberto, additional, Silberstein, John L., additional, Banuelos, Allison, additional, Dhingra, Shaurya, additional, Sotillo, Elena, additional, Heitzeneder, Sabine, additional, Tousley, Aidan, additional, Lattin, John, additional, Xu, Peng, additional, Huang, Jing, additional, Nasholm, Nicole, additional, Dalton, Guillermo Nicolas, additional, He, Andy, additional, Kuo, Tracy C., additional, Sangalang, Emma R.B., additional, Pons, Jaume, additional, Barkal, Amira, additional, Brewer, Rachel, additional, Marjon, Kristopher D., additional, Marshall, Payton L., additional, Fernandes, Ricardo, additional, Cochran, Jennifer R., additional, Sorensen, Poul H., additional, Daldrup-Link, Heike E., additional, Weissman, Irving L., additional, Sage, Julien, additional, Majeti, Ravindra, additional, Bertozzi, Carolyn R., additional, Weiss, William A., additional, Mackall, Crystal L., additional, and Majzner, Robbie G., additional
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- 2021
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116. Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery
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Chiou, Shin-Heng, primary, Tseng, Diane, additional, Reuben, Alexandre, additional, Mallajosyula, Vamsee, additional, Molina, Irene S., additional, Conley, Stephanie, additional, Wilhelmy, Julie, additional, McSween, Alana M., additional, Yang, Xinbo, additional, Nishimiya, Daisuke, additional, Sinha, Rahul, additional, Nabet, Barzin Y., additional, Wang, Chunlin, additional, Shrager, Joseph B., additional, Berry, Mark F., additional, Backhus, Leah, additional, Lui, Natalie S., additional, Wakelee, Heather A., additional, Neal, Joel W., additional, Padda, Sukhmani K., additional, Berry, Gerald J., additional, Delaidelli, Alberto, additional, Sorensen, Poul H., additional, Sotillo, Elena, additional, Tran, Patrick, additional, Benson, Jalen A., additional, Richards, Rebecca, additional, Labanieh, Louai, additional, Klysz, Dorota D., additional, Louis, David M., additional, Feldman, Steven A., additional, Diehn, Maximilian, additional, Weissman, Irving L., additional, Zhang, Jianjun, additional, Wistuba, Ignacio I., additional, Futreal, P. Andrew, additional, Heymach, John V., additional, Garcia, K. Christopher, additional, Mackall, Crystal L., additional, and Davis, Mark M., additional
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- 2021
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117. Isolated subarachnoid hemorrhage in mild traumatic brain injury: is a repeat CT scan necessary? A single-institution retrospective study
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Alessandro Moiraghi, Adrien May, Alberto Delaidelli, Gianpaolo Jannelli, Andrea Bartoli, Ramona Guatta, and Karl Lothard Schaller
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CT scan ,Male ,medicine.medical_specialty ,Neurology ,Subarachnoid hemorrhage ,Traumatic brain injury ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Subarachnoid Hemorrhage, Traumatic ,medicine ,Humans ,Glasgow Coma Scale ,Mild traumatic brain injury ,Traumatic subarachnoid hemorrhage ,Brain Concussion ,Neuroradiology ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Retrospective cohort study ,Interventional radiology ,Emergency department ,Subarachnoid Hemorrhage ,medicine.disease ,ddc:616.8 ,Surgery ,Female ,Neurology (clinical) ,Radiology ,Neurosurgery ,business ,Tomography, X-Ray Computed ,030217 neurology & neurosurgery - Abstract
Traumatic brain injury (TBI) with isolated subarachnoid hemorrhage (iSAH) is a common finding in the emergency department. In many centers, a repeat CT scan is routinely performed 24 to72 h following the trauma to rule out further radiological progression. The aim of this study is to assess the clinical utility of the repeat CT scan in clinical practice. We reviewed the medical charts of all patients who presented to our institution with mild TBI (mTBI) and isolated SAH between January 2015 and October 2017. CT scan at admission and control after 24 to 72 h were examined for each patient in order to detect any possible change. Neurological deterioration, antiplatelet/anticoagulant therapy, coagulopathy, SAH location, associated injuries, and length of stay in hospital were analyzed. Of the 649 TBI patients, 106 patients met the inclusion criteria. Fifty-four patients were females and 52 were males with a mean age of 68.2 years. Radiological iSAH progression was found in 2 of 106 (1.89) patients, and one of them was under antiplatelet therapy. No neurological deterioration was observed. Ten of 106 (9.4%) patients were under anticoagulation therapy, and 28 of 106 (26.4%) were under antiplatelet therapy. ISAH in mTBI seems to be a radiological stable entity over 72 h with no neurological deterioration. The clinical utility of a repeat head CT in such patients is questionable, considering its radiation exposure and cost. Regardless of anticoagulation/antiplatelet therapy, neurologic observation and symptomatic treatment solely could be a reasonable alternative.
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- 2020
118. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma
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Donovan, Laura K, Delaidelli, Alberto, Joseph, Sujith K, Bielamowicz, Kevin, Fousek, Kristen, Holgado, Borja L, Manno, Alex, Srikanthan, Dilakshan, Gad, Ahmed Z, Van Ommeren, Randy, Przelicki, David, Richman, Cory, Ramaswamy, Vijay, Daniels, Craig, Pallota, Jonelle G, Douglas, Tajana, Joynt, Alyssa C M, Haapasalo, Joonas, Nor, Carolina, Vladoiu, Maria C, Kuzan-Fischer, Claudia M, Garzia, Livia, Mack, Stephen C, Varadharajan, Srinidhi, Baker, Matthew L, Hendrikse, Liam, Ly, Michelle, Kharas, Kaitlin, Balin, Polina, Wu, Xiaochong, Qin, Lei, Huang, Ning, Guerreiro Stücklin, Ana, et al, and University of Zurich
- Subjects
10036 Medical Clinic ,1300 General Biochemistry, Genetics and Molecular Biology ,610 Medicine & health - Published
- 2020
119. Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors
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Shaurya Dhingra, Samuel H. Cheshier, Sabine Mueller, Stéphanie Puget, Marcel Kool, Siddhartha Mitra, Derek Yecies, Olivier Delattre, Michael C. Frühwald, Johanna Theruvath, Christopher Mount, Robbie G. Majzner, Sakina Zaidi, Didier Surdez, Louai Labanieh, Daniel Williamson, Poul H. Sorensen, Amaury Leruste, Franck Bourdeaut, Claus Moritz Graef, Alberto Delaidelli, Pascal Johann, Crystal L. Mackall, Michelle Monje, Elena Sotillo, Stefan M. Pfister, Sabine Heitzeneder, Peng Xu, Martin Hasselblatt, and Martina Finetti
- Subjects
Adult ,B7 Antigens ,medicine.medical_treatment ,T-Lymphocytes ,Central nervous system ,Mice, SCID ,medicine.disease_cause ,Cancer Vaccines ,Immunotherapy, Adoptive ,General Biochemistry, Genetics and Molecular Biology ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Fetus ,Mice, Inbred NOD ,medicine ,Animals ,Humans ,SMARCB1 ,Receptor ,Cells, Cultured ,Rhabdoid Tumor ,030304 developmental biology ,Injections, Intraventricular ,0303 health sciences ,Chemotherapy ,Receptors, Chimeric Antigen ,business.industry ,Brain Neoplasms ,Teratoma ,Brain ,Infant ,General Medicine ,Immunotherapy ,Xenograft Model Antitumor Assays ,3. Good health ,Radiation therapy ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Child, Preschool ,Cancer research ,Female ,business ,Carcinogenesis - Abstract
Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months(1,2). We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs.(3,4)), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT(5,6), B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3. BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.
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- 2020
120. AMPK activation protects astrocytes from hypoxia‑induced cell death
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Ines Bruns, Manuel Jäger, Alina C.M. Sittig, Michael W. Ronellenfitsch, Joachim P. Steinbach, M I Strecker, Sonja Heller, Leli Barialai, Nadja I Lorenz, Iris C. Mildenberger, Martin Voss, Michael C. Burger, Anna‑Luisa Luger, and Alberto Delaidelli
- Subjects
AMPK ,0301 basic medicine ,Adenosine monophosphate ,ischemia ,Thiophenes ,mTORC1 ,AMP-Activated Protein Kinases ,Deoxyglucose ,Protective Agents ,Oxidative Phosphorylation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genetics ,Humans ,Glycolysis ,Hypoxia ,Protein kinase A ,Neurons ,Cell Death ,Chemistry ,Kinase ,neural cells ,TOR Serine-Threonine Kinases ,Biphenyl Compounds ,Articles ,General Medicine ,Cell biology ,Glucose ,030104 developmental biology ,Pyrones ,Astrocytes ,030220 oncology & carcinogenesis ,Ribosomal protein s6 ,mTOR ,neuroprotection ,Neuroglia ,Adenosine triphosphate ,Signal Transduction - Abstract
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a major cellular energy sensor that is activated by an increase in the AMP/adenosine triphosphate (ATP) ratio. This causes the initiation of adaptive cellular programs, leading to the inhibition of anabolic pathways and increasing ATP synthesis. AMPK indirectly inhibits mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a serine/threonine kinase and central regulator of cell growth and metabolism, which integrates various growth inhibitory signals, such as the depletion of glucose, amino acids, ATP and oxygen. While neuroprotective approaches by definition focus on neurons, that are more sensitive under cell stress conditions, astrocytes play an important role in the cerebral energy homeostasis during ischemia. Therefore, the protection of astrocytic cells or other glial cells may contribute to the preservation of neuronal integrity and function. In the present study, it was thus hypothesized that a preventive induction of energy deprivation-activated signaling pathways via AMPK may protect astrocytes from hypoxia and glucose deprivation. Hypoxia-induced cell death was measured in a paradigm of hypoxia and partial glucose deprivation in vitro in the immortalized human astrocytic cell line SVG. Both the glycolysis inhibitor 2-deoxy-d-glucose (2DG) and the AMPK activator A-769662 induced the phosphorylation of AMPK, resulting in mTORC1 inhibition, as evidenced by a decrease in the phosphorylation of the target ribosomal protein S6 (RPS6). Treatment with both 2DG and A-769662 also decreased glucose consumption and lactate production. Furthermore, A-769662, but not 2DG induced an increase in oxygen consumption, possibly indicating a more efficient glucose utilization through oxidative phosphorylation. Hypoxia-induced cell death was profoundly reduced by treatment with 2DG or A-769662. On the whole, the findings of the present study demonstrate, that AMPK activation via 2DG or A-769662 protects astrocytes under hypoxic and glucose-depleted conditions.
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- 2020
121. RNA modifications in brain tumorigenesis
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Poul H. Sorensen, Albert Z. Huang, and Alberto Delaidelli
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Gene isoform ,Polyadenylation ,Carcinogenesis ,Review ,Biology ,medicine.disease_cause ,Brain tumors ,lcsh:RC346-429 ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,mRNA modifications ,Glioma ,Gene expression ,N6-methyladenosine (m6A) ,medicine ,Animals ,Humans ,RNA Processing, Post-Transcriptional ,lcsh:Neurology. Diseases of the nervous system ,Alternative polyadenylation (APA) ,Cell growth ,Brain Neoplasms ,Alternative splicing ,RNA ,medicine.disease ,Inosine ,Cell biology ,Neurology (clinical) ,Post-translational modifications - Abstract
RNA modifications are emerging as critical regulators in cancer biology, thanks to their ability to influence gene expression and the predominant protein isoforms expressed during cell proliferation, migration, and other pro-oncogenic properties. The reversibility and dynamic nature of post-transcriptional RNA modifications allow cells to quickly adapt to microenvironmental changes. Recent literature has revealed that the deregulation of RNA modifications can promote a plethora of developmental diseases, including tumorigenesis. In this review, we will focus on four key post-transcriptional RNA modifications which have been identified as contributors to the pathogenesis of brain tumors: m6A, alternative polyadenylation, alternative splicing and adenosine to inosine modifications. In addition to the role of RNA modifications in brain tumor progression, we will also discuss potential opportunities to target these processes to improve the dismal prognosis for brain tumors.
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- 2020
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122. Class I <scp>HDAC</scp> inhibitors enhance <scp>YB</scp> ‐1 acetylation and oxidative stress to block sarcoma metastasis
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Xue Qi Wang, Fan Zhang, Syam Prakash Somasekharan, Jordan Cran, Olivier Delattre, Melvin Pan, Christopher S. Hughes, Hongwei Cheng, Yemin Wang, Poul H. Sorensen, David G. Huntsman, Anna Mandinova, Amal El-Naggar, Hai-Feng Zhang, Shane Colborne, Yuzhuo Wang, Didier Surdez, Bo Rafn, Gian Luca Negri, Martin E. Gleave, Nancy Kedersha, Gregg B. Morin, and Alberto Delaidelli
- Subjects
sarcoma ,NF-E2-Related Factor 2 ,Pyridines ,Antineoplastic Agents ,Bone Neoplasms ,Sarcoma, Ewing ,YB‐1 ,medicine.disease_cause ,Biochemistry ,Article ,NRF2 ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Stress granule ,HDAC inhibitors ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,metastasis ,Neoplasm Metastasis ,Molecular Biology ,Cells, Cultured ,Cancer ,030304 developmental biology ,0303 health sciences ,Chemistry ,Post-translational Modifications, Proteolysis & Proteomics ,Acetylation ,Articles ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,NFE2L2 ,3. Good health ,Histone Deacetylase Inhibitors ,Oxidative Stress ,Metabolism ,HIF1A ,Metastatic Ewing Sarcoma ,Benzamides ,Cancer research ,Translational Activation ,Sarcoma ,030217 neurology & neurosurgery ,Oxidative stress ,Transcription Factors - Abstract
Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which identified the class I HDAC inhibitor MS‐275 as enhancing vulnerability to reactive oxygen species (ROS) in sarcoma cells. Mechanistically, MS‐275 inhibits YB‐1 deacetylation, decreasing its binding to 5′‐UTRs of NFE2L2 encoding the antioxidant factor NRF2, thereby reducing NFE2L2 translation and synthesis of NRF2 to increase cellular ROS. By global acetylomics, MS‐275 promotes rapid acetylation of the YB‐1 RNA‐binding protein at lysine‐81, blocking binding and translational activation of NFE2L2, as well as known YB‐1 mRNA targets, HIF1A, and the stress granule nucleator, G3BP1. MS‐275 dramatically reduces sarcoma metastasis in vivo, but an MS‐275‐resistant YB‐1K81‐to‐alanine mutant restores metastatic capacity and NRF2, HIF1α, and G3BP1 synthesis in MS‐275‐treated mice. These studies describe a novel function for MS‐275 through enhanced YB‐1 acetylation, thus inhibiting YB‐1 translational control of key cytoprotective factors and its pro‐metastatic activity., Class 1 HDAC inhibitors including MS‐275 inhibit the RNA binding protein YB‐1 by enhancing its acetylation. This reduces its affinity to mRNA targets under cellular stress, and decreases tumor cell fitness and metastatic capacity.
- Published
- 2019
123. BIOM-35. CLINICALLY TRACTABLE OUTCOME PREDICTION OF GROUP 3/4 MEDULLOBLASTOMA BASED ON TPD52 IMMUNOHISTOCHEMISTRY: A MULTICOHORT STUDY
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Alberto Delaidelli, Christopher Dunham, Mariarita Santi, Gian Luca Negri, Andreas von Deimling, Stefan Pfister, Marcel Kool, Vijay Ramaswamy, Andrey Korshunov, Michael Taylor, and Poul Sorensen
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
BACKGROUND International consensus and the 2021 WHO classification recognize eight molecular subgroups among Group 3/4 medulloblastoma (representing ~60% of tumors). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or other molecular parameters of high-risk for Group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk-stratification. PATIENTS AND METHODS We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three Group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Risk stratification and prediction capability were computed utilizing uni- and multivariate survival analysis. Newly developed risk classifiers including TPD52 IHC were compared to state-of-the-art risk stratification schemes in terms of prediction error, area under the time-dependent receiver operating characteristic (ROC) curves and C-statistic. Biomarker-driven prognostic stratification models identified were cross validated in different cohorts. RESULTS TPD52 IHC positivity represents a significant independent predictor of early relapse and death for Group 3/4 medulloblastoma (HRs between 3.67-26.7 [95% CIs between 1.00-706.23], p = 0.05, 0.017 and 0.0058). Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity is a predictive indicator of poor response to chemotherapy (HR 12.66 [95% CI 3.53-45.40], p < 0.0001), suggesting important implication for therapeutic choices. CONCLUSION The current study redefines the approach to risk-stratification in Group 3/4 medulloblastoma. Integration of TPD52 IHC in classification algorithms significantly improves outcome prediction and can be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
- Published
- 2021
124. CSIG-23. ELONGATION CONTROL OF mRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA ADAPTATION TO NUTRIENT DEPRIVATION
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Que Xi Wang, Poul H. Sorensen, Gian Luca Negri, Alberto Delaidelli, Gabriel Leprivier, Yue Zhou Huang, Christopher S. Hughes, and Betty Yao
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Medulloblastoma ,Cancer Research ,Nutrient ,Oncology ,medicine ,Neurology (clinical) ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,Adaptation ,Elongation ,Biology ,medicine.disease ,Cell biology - Abstract
Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We pefrormed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p< 0.05). Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.
- Published
- 2021
125. Abstract 1548: Potent activity of CAR T cells targeting the oncofetal protein GPC2 engineered to recognize low antigen density in neuroblastoma
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Jose G. Vilches-Moure, Hima Anbunathan, Ansuman T. Satpathy, Zhongyu Zhu, Dorota Klysz, Kevin R. Parker, Peng Xu, Elena Sotillo-Pineiro, Samantha Buongervino, Alberto Delaidelli, Johanna Theruvath, Dimiter S. Dimitrov, Crystal L. Mackall, Sabine Heitzeneder, Dontcho Jelev, Anya Alag, Jennifer Hwang, John M. Maris, Shaurya Dhingra, Kristopher R. Bosse, Jing Huang, Poul H. Sorensen, Martin Hasselblatt, Robbie G. Majzner, and Min Huang
- Subjects
Cancer Research ,Oncology ,Antigen ,Chemistry ,Neuroblastoma ,Cancer research ,medicine ,Car t cells ,medicine.disease - Abstract
Background: CAR T-cells targeting solid tumor antigens have not yet demonstrated similar success as seen for CD19, BCMA and CD22 in B-cell malignancies. Truly tumor-specific antigens are rare, yet pediatric solid tumors manifest stalled fetal developmental programs and often overexpress oncofetal antigens, normally restricted to prenatal tissues. Antigen density is a major factor determining CAR potency and whether such nonmutant antigens can be effectively and safely targeted remains unknown. Here, we engineered CAR T-cells targeting GPC2 to recognize clinically relevant antigen thresholds and assess safety. Methods: Expression of GPC2 was assessed during organ development (Cardoso-Moreira et al. 2019), by IHC in prenatal, infant and pediatric brain and in ssRNAseq datasets of fetal (La Manno et. al 2016) and adult brain (Allen Brain Atlas). To measure the molecules/cell of GPC2 and other immunotherapy-relevant targets on bone-marrow infiltrating neuroblastoma (NB) cells of high-risk patients, we developed a Flow Cytometric quantification assay and engineered GPC2-CAR T-cells to recognize relevant antigen thresholds. To assess binding specificity towards GPC2, a membrane proteome array encompassing >5,300 human proteins was utilized. Taking advantage of the murine cross-reactivity of our lead GPC2-CAR, toxicity was assessed in a relevant xenograft model. Results: During organ development, we found GPC2 expression restricted to the developing brain and a gradual decrease until silenced after birth. IHC of prenatal brain revealed an inverse correlation between GPC2 and gestational age (r = -0.775, p = 0.008) and very low staining in infant and pediatric brain (H-scores Conclusion: Our results demonstrate safety and efficacy of a lead GPC2-CAR and illuminate oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors. This work establishes a strong basis for testing GPC2 CAR T-cells in early phase clinical trials. Citation Format: Sabine Heitzeneder, Kristopher R. Bosse, Zhongyu Zhu, Dontcho Jelev, Shaurya Dhingra, Robbie Majzner, Elena Sotillo-Pineiro, Samantha Buongervino, Peng Xu, Jing Huang, Alberto Delaidelli, Martin Hasselblatt, Kevin Parker, Hima Anbunathan, Anya Alag, Jennifer Hwang, Min Huang, Dorota D. Klysz, Johanna L. Theruvath, Jose G. Vilches-Moure, Ansuman T. Satpathy, Poul H. Sorensen, Dimiter S. Dimitrov, John M. Maris, Crystal L. Mackall. Potent activity of CAR T cells targeting the oncofetal protein GPC2 engineered to recognize low antigen density in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1548.
- Published
- 2021
126. Abstract 6080: IL1RAP augments Cysteine metabolism and drives oxidative stress adaptation and lung metastasis in Ewing sarcoma
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Zhang, Hai-Feng, primary, El-Naggar, Amal M., additional, Cheng, Hongwei, additional, Prudova, Anna, additional, Delaidelli, Alberto, additional, He, Jian-Zhong, additional, Negri, Gian Luca, additional, Lizardo, Michael, additional, Yang, Tianqing, additional, Morin, Gregg, additional, Li, Wei, additional, Dimitrov, Dimiter S., additional, and Sorensen, Poul H., additional
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- 2020
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127. Abstract PR14: Ewing sarcoma cells exploit the IL1RAP-CTH axis to drive oxidative stress adaptation and lung metastasis
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Zhang, Haifeng, primary, El-Naggar, Amal M., additional, Cheng, Hongwei, additional, Delaidelli, Alberto, additional, Negri, Gian Luca, additional, Li, Wei, additional, Dimitrov, Dimiter S., additional, and Sorensen, Poul H.B., additional
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- 2020
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128. Abstract B27: A link between small noncoding RNAs and mRNA translation elongation: The let7-eEF2K axis in pediatric tumor adaptation to nutrient deprivation
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Delaidelli, Alberto, primary, Negri, Gian Luca, additional, Wang, Xue Qi, additional, Sidhu, Simran, additional, Cho, Brian, additional, Leprivier, Gabriel, additional, Hovestadt, Volker, additional, Pfister, Stefan, additional, Taylor, Michael, additional, Kool, Marcel, additional, and Sorensen, Poul, additional
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- 2020
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129. Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma
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Michealraj, Kulandaimanuvel Antony, primary, Kumar, Sachin A., additional, Kim, Leo J.Y., additional, Cavalli, Florence M.G., additional, Przelicki, David, additional, Wojcik, John B., additional, Delaidelli, Alberto, additional, Bajic, Andrea, additional, Saulnier, Olivier, additional, MacLeod, Graham, additional, Vellanki, Ravi N., additional, Vladoiu, Maria C., additional, Guilhamon, Paul, additional, Ong, Winnie, additional, Lee, John J.Y., additional, Jiang, Yanqing, additional, Holgado, Borja L., additional, Rasnitsyn, Alex, additional, Malik, Ahmad A., additional, Tsai, Ricky, additional, Richman, Cory M., additional, Juraschka, Kyle, additional, Haapasalo, Joonas, additional, Wang, Evan Y., additional, De Antonellis, Pasqualino, additional, Suzuki, Hiromichi, additional, Farooq, Hamza, additional, Balin, Polina, additional, Kharas, Kaitlin, additional, Van Ommeren, Randy, additional, Sirbu, Olga, additional, Rastan, Avesta, additional, Krumholtz, Stacey L., additional, Ly, Michelle, additional, Ahmadi, Moloud, additional, Deblois, Geneviève, additional, Srikanthan, Dilakshan, additional, Luu, Betty, additional, Loukides, James, additional, Wu, Xiaochong, additional, Garzia, Livia, additional, Ramaswamy, Vijay, additional, Kanshin, Evgeny, additional, Sánchez-Osuna, María, additional, El-Hamamy, Ibrahim, additional, Coutinho, Fiona J., additional, Prinos, Panagiotis, additional, Singh, Sheila, additional, Donovan, Laura K., additional, Daniels, Craig, additional, Schramek, Daniel, additional, Tyers, Mike, additional, Weiss, Samuel, additional, Stein, Lincoln D., additional, Lupien, Mathieu, additional, Wouters, Bradly G., additional, Garcia, Benjamin A., additional, Arrowsmith, Cheryl H., additional, Sorensen, Poul H., additional, Angers, Stephane, additional, Jabado, Nada, additional, Dirks, Peter B., additional, Mack, Stephen C., additional, Agnihotri, Sameer, additional, Rich, Jeremy N., additional, and Taylor, Michael D., additional
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- 2020
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130. AMPK activation protects astrocytes from hypoxia‑induced cell death
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Barialai, Leli, primary, Strecker, Maja, additional, Luger, Anna‑Luisa, additional, J�ger, Manuel, additional, Bruns, Ines, additional, Sittig, Alina, additional, Mildenberger, Iris, additional, Heller, Sonja, additional, Delaidelli, Alberto, additional, Lorenz, Nadja, additional, Voss, Martin, additional, Ronellenfitsch, Michael, additional, Steinbach, Joachim, additional, and Burger, Michael, additional
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- 2020
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131. Abstract LB-B04: A multi-omic surfaceome study identifies DLK1 as an epigenetically regulated protein and immunotherapeutic target in neuroblastoma
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Weiner, Amber K., primary, Radaoui, Alexander B., additional, Tsang, Matthew, additional, Martinez, Dan, additional, Sidoli, Simone, additional, Conkrite, Karina L., additional, Delaidelli, Alberto, additional, Rokita, Jo Lynne, additional, Lane, Maria V., additional, Vaksman, Zalman, additional, Rathi, Komal S., additional, Raman, Pichai, additional, Pogoriler, Jennifer, additional, Bhatti, Tricia, additional, Pawel, Bruce, additional, Teicher, Beverly, additional, Erickson, Stephen W., additional, Sorensen, Poul, additional, Mosse, Yael P., additional, Krytska, Kateryna, additional, Zammarchi, Francesca, additional, Berkel, Patrick H. van, additional, Smith, Malcolm A., additional, Garcia, Benjamin A., additional, Maris, John M., additional, and Diskin, Sharon J., additional
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- 2019
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132. Class I HDAC inhibitors enhance YB ‐1 acetylation and oxidative stress to block sarcoma metastasis
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El‐Naggar, Amal M, primary, Somasekharan, Syam Prakash, additional, Wang, Yemin, additional, Cheng, Hongwei, additional, Negri, Gian Luca, additional, Pan, Melvin, additional, Wang, Xue Qi, additional, Delaidelli, Alberto, additional, Rafn, Bo, additional, Cran, Jordan, additional, Zhang, Fan, additional, Zhang, Haifeng, additional, Colborne, Shane, additional, Gleave, Martin, additional, Mandinova, Anna, additional, Kedersha, Nancy, additional, Hughes, Christopher S, additional, Surdez, Didier, additional, Delattre, Olivier, additional, Wang, Yuzhuo, additional, Huntsman, David G, additional, Morin, Gregg B, additional, and Sorensen, Poul H, additional
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- 2019
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133. EMBR-21. CLINICALLY TRACTABLE OUTCOME PREDICTION OF GROUP 3/4 MEDULLOBLASTOMA BASED ON TPD52 IMMUNOHISTOCHEMISTRY: A MULTICOHORT STUDY
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Vijay Ramaswamy, Poul H. Sorensen, Michael D. Taylor, Olga Zheludkova, Marcel Kool, Mariarita Santi, Andrey Korshunov, Damian Stichel, Daniel Schrimpf, Andreas von Deimling, Marina Ryzhova, Joanna Triscott, Stefan M. Pfister, Andrey Golanov, Alberto Delaidelli, Christopher Dunham, Konstantin Okonechnikov, and Gian Luca Negri
- Subjects
Oncology ,Medulloblastoma ,Cancer Research ,medicine.medical_specialty ,business.industry ,Signs and symptoms ,medicine.disease ,Chemotherapy regimen ,Embryonal Tumors ,Internal medicine ,AcademicSubjects/MED00300 ,Medicine ,Immunohistochemistry ,AcademicSubjects/MED00310 ,Neurology (clinical) ,business ,Outcome prediction - Abstract
Background International consensus and the 2021 WHO classification recognize eight molecular subtypes among Group 3/4 medulloblastoma (representing ~60% of tumors). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or other molecular parameters of high-risk for Group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk-stratification. Patients and Methods We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three Group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Risk stratification and prediction capability were computed utilizing uni- and multivariate survival analysis. Newly developed risk classifiers including TPD52 IHC were compared to state-of-the-art risk stratification schemes in terms of prediction error, area under the time-dependent receiver operating characteristic (ROC) curves and C-statistic. Biomarker-driven prognostic stratification models identified were cross validated in different cohorts. Results TPD52 IHC positivity represents a significant independent predictor of early relapse and death for Group 3/4 medulloblastoma (HRs between 3.67–26.7 [95% CIs between 1.00–706.23], p = 0.05, 0.017 and 0.0058). Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity is a predictive indicator of poor response to chemotherapy (HR 12.66 [95% CI 3.53–45.40], p < 0.0001), suggesting important implication for therapeutic choices. Conclusion The current study redefines the approach to risk-stratification in Group 3/4 medulloblastoma. Integration of TPD52 IHC in classification algorithms significantly improves outcome prediction and can be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
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- 2021
134. EMBR-20. ELONGATION CONTROL OF MRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA
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Andrii Vislovukh, Yue Zhou Huang, Gabriel Leprivier, Betty Yao, Joyce Zhang, Volker Hovestadt, Simran Sidhu, Michael D. Taylor, Gian Luca Negri, Poul H. Sorensen, Que Xi Wang, Sofya Langman, Alberto Delaidelli, and Albert Z. Huang
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Medulloblastoma ,Untranslated region ,Cancer Research ,Intrinsic drive ,Three prime untranslated region ,Biology ,medicine.disease ,Cell biology ,Embryonal Tumors ,Oncology ,Downregulation and upregulation ,microRNA ,medicine ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Neurology (clinical) ,Metabolic Stress ,Elongation - Abstract
Medulloblastoma (MB) is the most common pediatric intracranial tumor and leading cause of childhood related cancer deaths. Group 3 affiliation and genetic amplifications of the MYC oncogene are predictors of adverse outcome in MB, underscoring a dire need for novel and more effective therapeutic approaches. The let-7 family of small non-coding RNAs (miRNAs) is known to inhibit tumor progression and regulate metabolism by targeting and degrading several cellular mRNAs, including MYC. Indeed, let-7 miRNAs are frequently repressed in several cancer types, including in MYC-driven MB. We previously reported that the mRNA translation elongation regulator eukaryotic Elongation Factor-2 Kinase (eEF2K) is a pivotal mediator of cancer cell adaptation to nutrient deprivation. In the current work, we identified a potential binding site for let-7 miRNAs on the eEF2K 3’ untranslated region (UTR). In addition, eEF2K mRNA and let-7 miRNA expressions negatively correlate in MB, suggesting a potential regulation of the former by the latter. Let-7 miRNAs transfection decreases eEF2K mRNA and protein levels (by ~40–50%). Down-regulation of luciferase activity by let-7 miRNAs is impaired upon mutation of the let-7 binding site on the eEF2K 3’UTR. Inhibition of eEF2K significantly reduces survival of MYC-amplified MB cell lines under nutrient deprivation, altering their mRNA translation rates. Knockout of eEF2K increases survival of MYC-amplified MB xenografts when mice are kept under calorie restricted diets. We conclude that let-7 miRNAs degrade the eEF2K mRNA by binding to its 3’UTR, indicating that let-7 repression in MYC-driven MB is partially responsible for increased eEF2K levels. Moreover, the let-7-eEF2K axis constitutes a critical mechanism for MYC-driven MB adaptation to acute metabolic stress, representing a promising therapeutic target. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs, as eEF2K activity appears critical under metabolic stress conditions.
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- 2021
135. MYCN amplified neuroblastoma requires the mRNA translation regulator eEF2 kinase to adapt to nutrient deprivation
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John M. Maris, Christopher J. Carnie, Asad Jan, Brandon Jansonius, Marc Remke, Poul H. Sorensen, Htoo Zarni Oo, Debjit Khan, Gian Luca Negri, Jonathan K M Lim, Alberto Delaidelli, Gabriel Leprivier, and Amal El-Naggar
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0301 basic medicine ,Tumor microenvironment ,Gene knockdown ,Cell growth ,Kinase ,HEK 293 cells ,Cell Biology ,Biology ,EEF2 ,medicine.disease ,N-Myc Proto-Oncogene Protein ,03 medical and health sciences ,030104 developmental biology ,Neuroblastoma ,Cancer research ,medicine ,neoplasms ,Molecular Biology - Abstract
MYC family proteins are implicated in many human cancers, but their therapeutic targeting has proven challenging. MYCN amplification in childhood neuroblastoma (NB) is associated with aggressive disease and high mortality. Novel and effective therapeutic strategies are therefore urgently needed for these tumors. MYC-driven oncogenic transformation impairs cell survival under nutrient deprivation (ND), a characteristic stress condition within the tumor microenvironment. We recently identified eukaryotic Elongation Factor 2 Kinase (eEF2K) as a pivotal mediator of the adaptive response of tumor cells to ND. We therefore hypothesized that eEF2K facilitates the adaptation of MYCN amplified NB to ND, and that inhibiting this pathway can impair MYCN-driven NB progression. To test our hypothesis, we first analyzed publicly available genomic databases and tissue microarrays for eEF2K expression in NB, and for links between eEF2K, MYCN, and clinical outcome in NB. Effects of eEF2K inhibition were evaluated on survival of MYCN amplified versus non-amplified NB cell lines under ND. Finally, NB xenograft mouse models were used to confirm in vitro observations. Our results indicate that high eEF2K expression and activity are strongly predictive of poor outcome in NB, and correlates significantly with MYCN amplification. Inhibition of eEF2K markedly decreases survival of MYCN amplified NB cell lines in vitro under ND. Growth of MYCN amplified NB xenografts is markedly impaired by eEF2K knockdown, particularly under caloric restriction. In summary, eEF2K protects MYCN overexpressing NB cells from ND in vitro and in vivo, highlighting this kinase as a critical mediator of the adaptive response of MYCN amplified NB cells to metabolic stress.
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- 2017
136. eEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response
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Forum Bhanshali, Stefan Taubert, Ian R. A. Mackenzie, Poul H. Sorensen, Don Moerman, Michael R. Hayden, Gian Luca Negri, Milène Vandal, Alberto Delaidelli, Frédéric Calon, Asad Jan, Syam Prakash Somasekharan, and Brandon Jansonius
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Elongation Factor 2 Kinase ,Male ,0301 basic medicine ,Cell Survival ,NF-E2-Related Factor 2 ,Hippocampus ,Neurotransmission ,Biology ,medicine.disease_cause ,Neuroprotection ,Pathology and Forensic Medicine ,Animals, Genetically Modified ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Alzheimer Disease ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Caenorhabditis elegans ,Cells, Cultured ,Neurons ,Gene knockdown ,Amyloid beta-Peptides ,Kelch-Like ECH-Associated Protein 1 ,Neurotoxicity ,medicine.disease ,KEAP1 ,Peptide Fragments ,Frontal Lobe ,Cell biology ,Oxidative Stress ,Neuroprotective Agents ,030104 developmental biology ,Biochemistry ,Synaptic plasticity ,Female ,Neurology (clinical) ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Soluble oligomers of amyloid-β (Aβ) impair synaptic plasticity, perturb neuronal energy homeostasis, and are implicated in Alzheimer's disease (AD) pathogenesis. Therefore, significant efforts in AD drug discovery research aim to prevent the formation of Aβ oligomers or block their neurotoxicity. The eukaryotic elongation factor-2 kinase (eEF2K) plays a critical role in synaptic plasticity, and couples neurotransmission to local dendritic mRNA translation. Recent evidence indicates that Aβ oligomers activate neuronal eEF2K, suggesting a potential link to Aβ induced synaptic dysfunction. However, a detailed understanding of the role of eEF2K in AD pathogenesis, and therapeutic potential of eEF2K inhibition in AD, remain to be determined. Here, we show that eEF2K activity is increased in postmortem AD patient cortex and hippocampus, and in the hippocampus of aged transgenic AD mice. Furthermore, eEF2K inhibition using pharmacological or genetic approaches prevented the toxic effects of Aβ42 oligomers on neuronal viability and dendrite formation in vitro. We also report that eEF2K inhibition promotes the nuclear factor erythroid 2-related factor (NRF2) antioxidant response in neuronal cells, which was crucial for the beneficial effects of eEF2K inhibition in neurons exposed to Aβ42 oligomers. Accordingly, NRF2 knockdown or overexpression of the NRF2 inhibitor, Kelch-Like ECH-Associated Protein-1 (Keap1), significantly attenuated the neuroprotection associated with eEF2K inhibition. Finally, genetic deletion of the eEF2K ortholog efk-1 reduced oxidative stress, and improved chemotaxis and serotonin sensitivity in C. elegans expressing human Aβ42 in neurons. Taken together, these findings highlight the potential utility of eEF2K inhibition to reduce Aβ-mediated oxidative stress in AD.
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- 2016
137. IMMU-05. COMBINATIONAL CAR T-CELL AND EPIGENETIC MODIFIER THERAPY TO TARGET POSTERIOR FOSSA TUMORS
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Poul Sorenson, Nabil Ahmed, Sujith K. Joseph, Alberto Delaidelli, Kevin Bielamowicz, Michael D. Taylor, and Laura K. Donovan
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Medulloblastoma ,Cancer Research ,business.industry ,Epigenetic modifier ,Azacitidine ,Immunology/Immunotherapy ,medicine.disease ,Posterior Fossa Tumors ,Chimeric antigen receptor ,Oncology ,Antigen ,medicine ,Cancer research ,Combined Modality Therapy ,Neurology (clinical) ,Epigenetics ,business ,medicine.drug - Abstract
Posterior Fossa tumours (PFTs) are the leading cause of cancer-related death in children, with medulloblastoma and ependymoma (EP) the most prevalent. PFTs continue to be treated with non-specific toxic therapies, with survivors suffering life threatening morbidities. PFTs are known to have distinct molecular sub-types; here we focus on two PFTs—Group 3 medulloblastoma and Posterior Fossa A (PFA) EP—which have the worst outcomes and are restricted to children. Actionable and recurrent mutations are rare in these PFTs; we recently confirmed the presence of three Chimeric Antigen Receptor (CAR) target antigens, EPHA2, HER2 and IL13R2, for use as mono-CARs, TRI CARs, and in combinational therapy with the epigenetic modifier Azacitidine. Pre-clinical trials showed CAR delivery via the lateral ventricle gave the most significant survival benefit (P500 days post therapy. Combination therapy of 1R EPHA2 CARs with Azacitidine gave significant tumor regression versus EPHA2 CARs alone (P
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- 2019
138. Navigated intraoperative 2-dimensional ultrasound in high-grade glioma surgery: impact on extent of resection and patient outcome
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Adrien May, Alessandro Moiraghi, Alberto Delaidelli, Karl Lothard Schaller, Andrea Bartoli, Francesco DiMeco, Alessandro Perin, Ramona Guatta, Marco Saini, Shahan Momjian, Francesco Prada, Thomas Wälchli, and Philippe Bijlenga
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medicine.medical_specialty ,Neuronavigation ,Extent of resection ,Preoperative care ,Intraoperative ultrasound ,Glioma ,Humans ,Medicine ,Gliomas ,High-grade gliomas ,Retrospective Studies ,Ultrasonography ,High-Grade Glioma ,medicine.diagnostic_test ,Brain Neoplasms ,business.industry ,Ultrasound ,Magnetic resonance imaging ,medicine.disease ,Patient outcome ,ddc:616.8 ,Surgery ,Neurology (clinical) ,Radiology ,Residual tumor volume ,business - Abstract
Maximizing extent of resection (EOR) and reducing residual tumor volume (RTV) while preserving neurological functions is the main goal in the surgical treatment of gliomas. Navigated intraoperative ultrasound (N-ioUS) combining the advantages of ultrasound and conventional neuronavigation (NN) allows for overcoming the limitations of the latter.To evaluate the impact of real-time NN combining ioUS and preoperative magnetic resonance imaging (MRI) on maximizing EOR in glioma surgery compared to standard NN.We retrospectively reviewed a series of 60 cases operated on for supratentorial gliomas: 31 operated under the guidance of N-ioUS and 29 resected with standard NN. Age, location of the tumor, pre- and postoperative Karnofsky Performance Status (KPS), EOR, RTV, and, if any, postoperative complications were evaluated.The rate of gross total resection (GTR) in NN group was 44.8% vs 61.2% in N-ioUS group. The rate of RTV 1 cm3 for glioblastomas was significantly lower for the N-ioUS group (P .01). In 13/31 (42%), RTV was detected at the end of surgery with N-ioUS. In 8 of 13 cases, (25.8% of the cohort) surgeons continued with the operation until complete resection. Specificity was greater in N-ioUS (42% vs 31%) and negative predictive value (73% vs 54%). At discharge, the difference between pre- and postoperative KPS was significantly higher for the N-ioUS (P .01).The use of an N-ioUS-based real-time has been beneficial for resection in noneloquent high-grade glioma in terms of both EOR and neurological outcome, compared to standard NN. N-ioUS has proven usefulness in detecting RTV 1 cm3.
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- 2019
139. Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically
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Shawn C. Chafe, Paul C. McDonald, Alastair H. Kyle, Youwen Zhou, Andrew I. Minchinton, Jordan A. Gillespie, Sohrab P. Shah, Oksana Nemirovsky, Saeed Saberi, Ali Bashashati, Shoukat Dedhar, Jennifer H.E. Baker, Geetha Venkateswaran, Dongxia Gao, Samantha Burugu, and Alberto Delaidelli
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Cancer Research ,Lung Neoplasms ,Immunology ,Programmed Cell Death 1 Receptor ,Apoptosis ,Breast Neoplasms ,Gene Expression Regulation, Enzymologic ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Antineoplastic Agents, Immunological ,Tumor Cells, Cultured ,Tumor Microenvironment ,Medicine ,Animals ,Humans ,CTLA-4 Antigen ,Hypoxia ,Survival rate ,Melanoma ,Carbonic Anhydrases ,Cell Proliferation ,Tumor microenvironment ,Sulfonamides ,business.industry ,Phenylurea Compounds ,medicine.disease ,Prognosis ,Immune checkpoint ,3. Good health ,Blockade ,Mice, Inbred C57BL ,Survival Rate ,Cell killing ,030220 oncology & carcinogenesis ,Enzyme Induction ,Cancer research ,Drug Therapy, Combination ,Female ,business ,030215 immunology - Abstract
Treatment strategies involving immune-checkpoint blockade (ICB) have significantly improved survival for a subset of patients across a broad spectrum of advanced solid cancers. Despite this, considerable room for improving response rates remains. The tumor microenvironment (TME) is a hurdle to immune function, as the altered metabolism-related acidic microenvironment of solid tumors decreases immune activity. Here, we determined that expression of the hypoxia-induced, cell-surface pH regulatory enzyme carbonic anhydrase IX (CAIX) is associated with worse overall survival in a cohort of 449 patients with melanoma. We found that targeting CAIX with the small-molecule SLC-0111 reduced glycolytic metabolism of tumor cells and extracellular acidification, resulting in increased immune cell killing. SLC-0111 treatment in combination with immune-checkpoint inhibitors led to the sensitization of tumors to ICB, which led to an enhanced Th1 response, decreased tumor growth, and reduced metastasis. We identified that increased expression of CA9 is associated with a reduced Th1 response in metastatic melanoma and basal-like breast cancer TCGA cohorts. These data suggest that targeting CAIX in the TME in combination with ICB is a potential therapeutic strategy for enhancing response and survival in patients with hypoxic solid malignancies.
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- 2018
140. PDTM-02. STRESS GRANULES ARE INDUCED BY OXIDATIVE STRESS IN PEDIATRIC BRAIN TUMORS AND PREDICT POOR OUTCOME
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Poul H. Sorensen, Gian Luca Negri, Alberto Delaidelli, Brian Cho, Sean Minaker, Mariarita Santi, John M. Maris, Amal M. El Naggar, Stephen Yip, and Juliette Hukin
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Oncology ,Cancer Research ,medicine.medical_specialty ,Tissue microarray ,business.industry ,Objective (goal) ,medicine.disease_cause ,medicine.disease ,Abstracts ,Stress granule ,Pediatric brain ,Internal medicine ,medicine ,Immunohistochemistry ,Neurology (clinical) ,Sarcoma ,business ,Oxidative stress ,Glioblastoma - Abstract
BACKGROUND/OBJECTIVES: Brain tumors represent the most common and aggressive pediatric cancer type, underscoring a dire need for novel therapeutic approaches. Tumors are continually exposed to acute changes in their microenvironment, including oxidative stress. To overcome acute stress, cells form stress granules (SGs), clusters of RNA and RNA-binding proteins (RBPs) that rapidly alter the cellular mRNA translation landscape. Preliminary data indicate that pharmacological inhibition of SG formation blocks the antioxidant response of the transcription factor NRF2 (NFE2L2), impairing pediatric sarcoma invasive and metastatic capacity. We therefore set out to determine if pediatric brain tumors rely on SGs to overcome oxidative stress, and if targeting SGs could represent a therapeutic approach for these tumors. METHODS: We analyzed public databases for links between mRNA expression of the RBP G3BP1 and NFE2L2. Immunohistochemistry (IHC) for G3BP1, NRF2 and oxidative stress markers (4HNE) was performed on atypical theratoid rabdoid tumor (AT/RT), pediatric glioblastoma (pGBM) and ependymoma (EPN) tissue microarrays. AT/RT, pGBM and EPN cell lines were treated with NaAsO(2) and H(2)O(2) to induce oxidative stress and SG presence was determined by ImmunoFluorescence for the RBPs G3BP1 and TIA-1. RESULTS: G3BP1 and NFE2L2 expression positively correlates in several pediatric tumor cohorts, including AT/RT, pGBM and EPN (p
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- 2018
141. Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery
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Sukhmani K. Padda, Alexandre Reuben, Mark M. Davis, Alana McSween, Xinbo Yang, Daisuke Nishimiya, Patrick Tran, P. Andrew Futreal, Julie Wilhelmy, Diane Tseng, Irene S. Molina, Jalen Benson, Natalie S. Lui, Heather A. Wakelee, Irving L. Weissman, John V. Heymach, Barzin Y. Nabet, Mark F. Berry, Joel W. Neal, K. Christopher Garcia, Rebecca Richards, Leah M. Backhus, Vamsee Mallajosyula, Poul H. Sorensen, Crystal L. Mackall, Elena Sotillo, Dorota Klysz, Ignacio I. Wistuba, Shin Heng Chiou, David M. Louis, Chunlin Wang, Alberto Delaidelli, Rahul Sinha, Joseph B. Shrager, Steven A. Feldman, Louai Labanieh, Stephanie D. Conley, Maximilian Diehn, Jianjun Zhang, and Gerald J. Berry
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0301 basic medicine ,Resource ,EntS ,Lung Neoplasms ,cross-reactivity ,T cell ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,Immunology ,Epitopes, T-Lymphocyte ,T-Cell Antigen Receptor Specificity ,Human leukocyte antigen ,Computational biology ,Biology ,Cross Reactions ,NSCLC ,Epitope ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,EBV ,LMP2A ,Antigens, Neoplasm ,tumor-infiltrating lymphocyte ,Carcinoma, Non-Small-Cell Lung ,HLA-A2 Antigen ,medicine ,Immunology and Allergy ,cancer ,Humans ,TMEM161A ,Cells, Cultured ,Antigen Presentation ,Tumor-infiltrating lymphocytes ,T-cell receptor ,Cancer ,medicine.disease ,T cell specificity ,GLIPH2 ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Paratope ,T cell receptor repertoire ,TCR ,Algorithms ,Epitope Mapping ,Protein Binding - Abstract
Summary To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer., Graphical abstract, Highlights • The algorithm GLIPH2 enables analysis of shared TCR specificity and HLA prediction • Tumor-infiltrating T cells cross-react to EBV antigens and shared tumor antigens • EBV-specific T cells expanded in patients responding to immune checkpoint blockade • Cross-reactive CD8 T cells express GZMK, Chiou, Tseng, et al. analyze TCRβ chain sequences from 178 non-small cell lung cancer patients and identify shared specificity groups, which in turn enable antigen identification. One such antigenic epitope—a peptide from an epithelial protein—is cross-reactive to epitopes from Epstein-Barr virus and E. coli, suggesting that cross-reactivity may underlie the presence of pathogen-specific T cells in tumor infiltrates.
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- 2021
142. Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication
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Theruvath, Johanna, Menard, Marie, Smith, Benjamin A. H., Linde, Miles H., Coles, Garry L., Dalton, Guillermo Nicolas, Wu, Wei, Kiru, Louise, Delaidelli, Alberto, Sotillo, Elena, Silberstein, John L., Geraghty, Anna C., Banuelos, Allison, Radosevich, Molly Thomas, Dhingra, Shaurya, Heitzeneder, Sabine, Tousley, Aidan, Lattin, John, Xu, Peng, Huang, Jing, Nasholm, Nicole, He, Andy, Kuo, Tracy C., Sangalang, Emma R. B., Pons, Jaume, Barkal, Amira, Brewer, Rachel E., Marjon, Kristopher D., Vilches-Moure, Jose G., Marshall, Payton L., Fernandes, Ricardo, Monje, Michelle, Cochran, Jennifer R., Sorensen, Poul H., Daldrup-Link, Heike E., Weissman, Irving L., Sage, Julien, Majeti, Ravindra, Bertozzi, Carolyn R., Weiss, William A., Mackall, Crystal L., and Majzner, Robbie G.
- Abstract
The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called ‘Don’t eat me’ signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic ‘Eat me’ signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.
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- 2022
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143. Respiration: A New Mechanism for CSF Circulation?
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Alberto Delaidelli and Alessandro Moiraghi
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Adult ,Male ,Journal Club ,Cerebral Ventricles ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Respiration ,Image Processing, Computer-Assisted ,Humans ,Medicine ,Cerebrospinal Fluid ,Brain Ventricle ,business.industry ,General Neuroscience ,Brain ,Anatomy ,Middle Aged ,Magnetic Resonance Imaging ,humanities ,CSF circulation ,Spinal Cord ,Cerebrovascular Circulation ,030221 ophthalmology & optometry ,Female ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
CSF flux is involved in the pathophysiology of neurodegenerative diseases and cognitive impairment after traumatic brain injury, all hallmarked by the accumulation of cellular metabolic waste. Its effective disposal via various CSF routes has been demonstrated in animal models. In contrast, the CSF dynamics in humans are still poorly understood. Using novel real-time MRI, forced inspiration has been identified recently as a main driving force of CSF flow in the human brain. Exploiting technical advances toward real-time phase-contrast MRI, the current work analyzed directions, velocities, and volumes of human CSF flow within the brain aqueduct as part of the internal ventricular system and in the spinal canal during respiratory cycles. A consistent upward CSF movement toward the brain in response to forced inspiration was seen in all subjects at the aqueduct, in 11/12 subjects at thoracic level 2, and in 4/12 subjects at thoracic level 5. Concomitant analyses of CSF dynamics and cerebral venous blood flow, that is, in epidural veins at cervical level 3, uniquely demonstrated CSF and venous flow to be closely communicating cerebral fluid systems in which inspiration-induced downward flow of venous blood due to reduced intrathoracic pressure is counterbalanced by an upward movement of CSF. The results extend our understanding of human CSF flux and open important clinical implications, including concepts for drug delivery and new classifications and therapeutic options for various forms of hydrocephalus and idiopathic intracranial hypertension.
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- 2017
144. Abstract 6080: IL1RAP augments Cysteine metabolism and drives oxidative stress adaptation and lung metastasis in Ewing sarcoma
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Anna Prudova, Amal El-Naggar, Hongwei Cheng, Alberto Delaidelli, Michael M. Lizardo, Jian-Zhong He, Tianqing Yang, Dimiter S. Dimitrov, Hai-Feng Zhang, Poul H. Sorensen, Wei Li, Gian Luca Negri, and Gregg B. Morin
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Cancer Research ,Lung metastasis ,Biology ,medicine.disease ,medicine.disease_cause ,chemistry.chemical_compound ,Oncology ,chemistry ,Cancer research ,medicine ,Sarcoma ,Adaptation ,Oxidative stress ,Cysteine metabolism - Abstract
The high oxidative stress cancer cells experience during the metastatic cascade is an important determinant of metastasis. How cancer cells adapt to those stressful conditions remains elusive. Here our global translatome and proteome analyses have uncovered novel signatures exploited by oncogene-transformed cells to adapt and survive oxidative stress. We revealed that various oncoproteins promote the expression of the IL1RAP to alleviate oxidative stress and facilitate stress adaptation. Mechanistically, IL1RAP controls Cysteine metabolism, a key substrate and determinant of antioxidant glutathione synthesis. CTH, a crucial enzyme for de novo Cysteine synthesis and redox regulation, was identified as a key functional mediator of IL1RAP. Moreover, global interactome analysis uncovered IL1RAP as a novel component and enhancer of the System Xc− transporter (SLC7A11), which is involved in Cystine uptake. Thus, IL1RAP enhances Cysteine supply via both uptake and biogenesis. IL1RAP depletion rendered Ewing sarcoma cells susceptible to oxidative stress and ferroptosis in vitro, and dramatically mitigated local invasion and lung metastasis in mice. In patients with Ewing sarcoma, high-expression of IL1RAP in the tumors correlated with poor event-free survival. Therefore, we have defined a novel pro-metastatic mechanism driven by IL1RAP-mediated Cysteine metabolism and redox regulation. Citation Format: Hai-Feng Zhang, Amal M. El-Naggar, Hongwei Cheng, Anna Prudova, Alberto Delaidelli, Jian-Zhong He, Gian Luca Negri, Michael Lizardo, Tianqing Yang, Gregg Morin, Wei Li, Dimiter S. Dimitrov, Poul H. Sorensen. IL1RAP augments Cysteine metabolism and drives oxidative stress adaptation and lung metastasis in Ewing sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6080.
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- 2020
145. Abstract PR14: Ewing sarcoma cells exploit the IL1RAP-CTH axis to drive oxidative stress adaptation and lung metastasis
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Dimiter S. Dimitrov, Hongwei Cheng, Gian Luca Negri, Amal El-Naggar, Wei Li, Poul H. Sorensen, Hai-Feng Zhang, and Alberto Delaidelli
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Cancer Research ,Nicotinic acid adenine dinucleotide phosphate ,Thapsigargin ,Chemistry ,Endoplasmic reticulum ,Synaptic vesicle ,Adenosine ,Neuromuscular junction ,Cell biology ,chemistry.chemical_compound ,medicine.anatomical_structure ,Oncology ,Second messenger system ,medicine ,Neurosecretion ,medicine.drug - Abstract
Metastasis is a highly inefficient process due to the high oxidative stress that cancer cells experience, such as in the circulation and at distant organs prior to colonization. How cancer cells adapt to those stressful conditions and develop anti-anoikis properties remains elusive. Here our global translatome and proteome analyses have uncovered novel signatures exploited by oncogene-transformed cells to adapt and survive anoikis-inducing stress. We reveal that EWS-ETS chimeric oncoproteins trigger the expression of the IL1RAP surface protein to alleviate oxidative stress and facilitate stress adaptation, thereby promoting lung metastasis in Ewing sarcoma. Proteomic profiling identifies CTH, a key enzyme for de novo cysteine synthesis and redox regulation, as an important functional downstream mediator of IL1RAP. Blockade of either IL1RAP or CTH, using genetic or pharmacologic approaches, renders EWS cells susceptible to oxidative stress in vitro, and dramatically mitigates primary tumor growth, local invasion and lung metastasis in mice. Importantly, high expression of this IL1RAP-CTH axis correlates with markedly decreased overall and event-free survival in EWS patients. Thus, our study has defined a novel mechanism exploited by EWS cells for metastasis, which can be a potential therapeutic target for high-risk metastatic EWS. This abstract is also being presented as Poster B58. Citation Format: Haifeng Zhang, Amal M. El-Naggar, Hongwei Cheng, Alberto Delaidelli, Gian Luca Negri, Wei Li, Dimiter S. Dimitrov, Poul H.B. Sorensen. Ewing sarcoma cells exploit the IL1RAP-CTH axis to drive oxidative stress adaptation and lung metastasis [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR14.
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- 2020
146. Abstract B27: A link between small noncoding RNAs and mRNA translation elongation: The let7-eEF2K axis in pediatric tumor adaptation to nutrient deprivation
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Gabriel Leprivier, Simran Sidhu, Volker Hovestadt, Michael D. Taylor, Marcel Kool, Stefan M. Pfister, Poul H. Sorensen, Gian Luca Negri, Alberto Delaidelli, Brian Cho, and Xue Qi Wang
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Untranslated region ,Cancer Research ,Gene knockdown ,Oncology ,Downregulation and upregulation ,Tumor progression ,Polysome ,microRNA ,Cancer research ,Transfection ,Biology ,Pediatric cancer - Abstract
Background: Medulloblastoma (MB) and neuroblastoma (NB) are the most common pediatric solid cancers and the leading cause of childhood cancer-related deaths. Genetic amplifications of the MYC and MYCN oncogenes are the strongest independent predictor of adverse outcomes in MB and NB, underscoring a dire need to improve therapeutic approaches. Tumors continually weather stress from acute microenvironmental changes, including limited nutrient availability. The let-7 family of small noncoding RNAs (miRNAs) inhibits tumor progression and regulates metabolism by selectively targeting and degrading mRNAs, including MYC and MYCN. Indeed, let-7 miRNAs are frequently repressed in several cancers, including in MYC-driven MB and NB. We previously reported that the mRNA translation elongation regulator eukaryotic eEF2K is a pivotal mediator of cancer cell adaptation to nutrient deprivation. Our preliminary data indicate that the eEF2K 3´ untranslated region (UTR) harbors a potential binding site for let-7 miRNAs. In addition, eEF2K mRNA and let-7 miRNA expressions negatively correlate in MB and NB. We therefore hypothesized that let-7 downregulation induces eEF2K expression, thereby supporting MYC-driven MB and NB adaptation to nutrient deprivation and tumor progression. Methods: Effects of eEF2K pharmacologic and genetic inhibition on MB and NB cell death were evaluated in vitro by flow cytometry, while cellular mRNA translation rates were studied by polysome fractionation and Click chemistry. The ability of let-7 to degrade eEF2K mRNA was assessed by let-7 miRNAs transfection into MB cells, followed by RT-PCR and Western blotting for eEF2K. Binding of let-7 to the eEF2K 3´UTR was validated by luciferase reporter assay. Finally, NB xenograft mouse models confirmed in vitro observations. Results: Inhibition of eEF2K significantly reduces survival of MYC/MYCN-amplified NB and MB cell lines under nutrient deprivation, altering their mRNA translation rates. Let-7 miRNAs transfection decreases eEF2K mRNA and protein levels by 40-50%. Downregulation of luciferase activity by let-7 miRNAs is impaired upon mutation of the let-7 binding site on the eEF2K 3´UTR. eEF2K knockdown decreases growth twofold in MYCN-amplified NB xenografts in mice under calorie-restriction diets. Conclusions: Let-7 miRNAs degrade the eEF2K mRNA by binding to its 3´UTR, indicating that let-7 repression in MYC-driven NB and MB is partially responsible for increased eEF2K levels. Moreover, the let-7-eEF2K axis constitutes a critical mechanism for MYC-driven MB and NB adaptation to acute metabolic stress, representing a promising therapeutic target. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs, as eEF2K activity appears critical under metabolic stress conditions. Citation Format: Alberto Delaidelli, Gian Luca Negri, Xue Qi Wang, Simran Sidhu, Brian Cho, Gabriel Leprivier, Volker Hovestadt, Stefan Pfister, Michael Taylor, Marcel Kool, Poul Sorensen. A link between small noncoding RNAs and mRNA translation elongation: The let7-eEF2K axis in pediatric tumor adaptation to nutrient deprivation [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B27.
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- 2020
147. Abstract LB-B04: A multi-omic surfaceome study identifies DLK1 as an epigenetically regulated protein and immunotherapeutic target in neuroblastoma
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Benjamin A. Garcia, Simone Sidoli, Yael P. Mosse, Matthew Tsang, Maria Lane, Jo Lynne Rokita, Francesca Zammarchi, Sharon J. Diskin, Jennifer Pogoriler, Daniel Martinez, Alexander B. Radaoui, Amber K. Weiner, Alberto Delaidelli, Bruce R. Pawel, Tricia R. Bhatti, Kateryna Krytska, Patrick Van Berkel, Komal S. Rathi, Malcolm A. Smith, Zalman Vaksman, Pichai Raman, Karina L. Conkrite, John M. Maris, Beverly A. Teicher, Poul H. Sorensen, and Stephen W. Erickson
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Cancer Research ,medicine.diagnostic_test ,Cell growth ,Cell ,Biology ,Immunofluorescence ,medicine.disease ,Molecular biology ,Flow cytometry ,medicine.anatomical_structure ,Oncology ,Membrane protein ,Cell culture ,Neuroblastoma ,medicine ,Chromatin immunoprecipitation - Abstract
Background: Neuroblastoma (NB) is an embryonal tumor of the sympathetic nervous system that accounts for 12% of childhood cancer deaths. While the introduction of GD2 immunotherapy provides an improvement in time to progression, the therapy is toxic and impact on overall survival is minimal, supporting an urgent need for novel immunotherapies. To date, the cell surface landscape (surfaceome) of NB remains undefined, hindering the identification of immunotherapeutic targets. Methods: To identify NB surfaceome proteins, we performed plasma membrane protein extraction using sucrose gradient ultracentrifugation coupled to mass spectrometry (nLC-MS/MS) in NB cell lines (n=12) and patient derived xenografts (PDX; n=10). These data were integrated with existing RNA-sequencing (NB=153; Normal=7859) and H3K27ac chromatin immunoprecipitation (ChIP)-sequencing data (from overlapping NB cell lines) to evaluate extracellular proteins differentially expressed in NB compared to normal tissues. Candidate targets were validated by immunohistochemistry on NB tumor and normal tissue microarrays (TMAs), flow cytometry and immunofluorescence. In-vitro functional studies were performed following genetic manipulation of candidate targets to assess cell proliferation, differentiation and viability. Finally, we tested ADCT-701 (a DLK1-directed antibody drug conjugate [ADC] with a pyrrolobenzodiazepine [PBD] warhead) in eight PDX models (study ongoing, total of 12 models initiated) with varying levels of DLK1 expression. At enrollment, two mice were each treated with a single dose of saline or 1mg/kg of B12-PL1601 (non-targeting PBD-conjugated ADC) or 1mg/kg ADCT-701 and mice were evaluated for 100 days or until tumor reached 2.0cm3. Results: We yielded on average 66% (range:60-68%) membrane protein enrichment with high reproducibility between biological replicates (80%; range:78-84%) and identified 4826 unique membrane proteins. Our approach confirmed known cell surface proteins in development as immunotherapeutic targets in NB (ALK, GPC2, NCAM1, DLL3 and CD276). Here, we prioritized DLK1 for further evaluation due to it being the only candidate with expression directly associated with a super enhancer element (P=6.09X10-5). RNA-sequencing and tissue microarray analysis of NB and normal tissues showed DLK1 to be overexpressed in a large subset of high-risk NB with minimal expression in normal tissues, excepting adrenal medulla and pituitary. Flow cytometry and immunofluorescence confirmed cell surface expression of DLK1 in a panel of NB cell lines. Genetic depletion of DLK1 using shRNA resulted in neurite outgrowth (P=7.26X10-5) and terminal differentiation. Full proteome analysis of DLK1 knockdown and control cell lines using MS showed regulation of proteins that control outgrowth of neurites (P=3.37X10-3) and development of neurons (P=3.76X10-3). To date, ADCT-701 treatment resulted in maintained complete response (N=2), complete response (N=3) and stable disease (N=1) in models with high DLK1 expression, while those with low/no expression showed disease progression (N=2). Conclusion: DLK1 is an epigenetically regulated immunotherapeutic target in neuroblastoma. ADCT-701 shows potent activity in preclinical models of NB and should be prioritized for clinical development. Citation Format: Amber K. Weiner, Alexander B. Radaoui, Matthew Tsang, Dan Martinez, Simone Sidoli, Karina L. Conkrite, Alberto Delaidelli, Jo Lynne Rokita, Maria V. Lane, Zalman Vaksman, Komal S. Rathi, Pichai Raman, Jennifer Pogoriler, Tricia Bhatti, Bruce Pawel, Beverly Teicher, Stephen W. Erickson, Poul Sorensen, Yael P. Mosse, Kateryna Krytska, Francesca Zammarchi, Patrick H. van Berkel, Malcolm A. Smith, Benjamin A. Garcia, John M. Maris, Sharon J. Diskin. A multi-omic surfaceome study identifies DLK1 as an epigenetically regulated protein and immunotherapeutic target in neuroblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B04. doi:10.1158/1535-7163.TARG-19-LB-B04
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- 2019
148. Translational control in brain pathologies: biological significance and therapeutic opportunities
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Poul H. Sorensen, Asad Jan, Alberto Delaidelli, and Jochen Herms
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0301 basic medicine ,mRNA translation ,pathology [Brain Neoplasms] ,Central nervous system ,RNA-binding protein ,RNA-binding proteins ,metabolism [Neurodegenerative Diseases] ,Biology ,metabolism [RNA-Binding Proteins] ,metabolism [RNA, Messenger] ,Brain tumors ,Pathology and Forensic Medicine ,genetics [RNA, Messenger] ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,pathology [Brain] ,medicine ,Protein biosynthesis ,MRNA transport ,Humans ,genetics [RNA-Binding Proteins] ,ddc:610 ,RNA, Messenger ,Control (linguistics) ,Translation control ,Messenger RNA ,Brain Neoplasms ,Neurodegenerative diseases ,pathology [Neurodegenerative Diseases] ,neurodegeneration ,eEF2 kinase ,Brain ,RNA-Binding Proteins ,Translation (biology) ,Neurodegenerative Diseases ,eEF2K ,metabolism [Brain Neoplasms] ,genetics [Brain Neoplasms] ,030104 developmental biology ,medicine.anatomical_structure ,metabolism [Brain] ,genetics [Neurodegenerative Diseases] ,Protein Biosynthesis ,Neurology (clinical) ,Neuroscience ,Nucleus ,030217 neurology & neurosurgery - Abstract
Messenger RNA (mRNA) translation is the terminal step in protein synthesis, providing a crucial regulatory checkpoint for this process. Translational control allows specific cell types to respond to rapid changes in the microenvironment or to serve specific functions. For example, neurons use mRNA transport to achieve local protein synthesis at significant distances from the nucleus, the site of RNA transcription. Altered expression or functions of the various components of the translational machinery have been linked to several pathologies in the central nervous system. In this review, we provide a brief overview of the basic principles of mRNA translation, and discuss alterations of this process relevant to CNS disease conditions, with a focus on brain tumors and chronic neurological conditions. Finally, synthesizing this knowledge, we discuss the opportunities to exploit the biology of altered mRNA translation for novel therapies in brain disorders, as well as how studying these alterations can shed new light on disease mechanisms.
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- 2018
149. Navigated Intraoperative 2D Ultrasound in High-Grade Glioma Surgery: Impact on Extent of Resection and Patient Outcome
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Adrien May, Karl Lothard Schaller, Ramona Guatta, Alessandro Moiraghi, Philippe Bijlenga, Alberto Delaidelli, F. DiMeco, F. Prada, Marco Saini, and Andrea Bartoli
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medicine.medical_specialty ,business.industry ,medicine ,2d ultrasound ,business ,Extent of resection ,Outcome (game theory) ,Surgery ,High-Grade Glioma - Published
- 2018
150. Additional file 1: of Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity
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Jan, Asad, Jansonius, Brandon, Delaidelli, Alberto, Forum Bhanshali, An, Yi, Ferreira, Nelson, Smits, Lisa, Negri, Gian, Schwamborn, Jens, Jensen, Poul, Mackenzie, Ian, Taubert, Stefan, and Sorensen, Poul
- Abstract
Table S1. Control and PD cases; Figure S1. Melanin bleaching in postmortem midbrain sections and immunostaining for phospho-eEF2 (p-eEF2, Thr56); Figure S2. Immunostaining for phospho-eEF2 (p-eEF2, Thr56) and phospho-AS (p-ASyn, Ser129) in postmortem control midbrain sections; Figure S3. Immunostaining for phospho-eEF2 (p-eEF2, Thr56) and phospho-AS (p-ASyn, Ser129) in postmortem PD midbrain sections; Figure S4. Detection of phospho-eEF2 (p-eEF2, Thr56) and phospho-AS (p-ASyn, Ser129) in postmortem control and PD midbrain sections by immunofluorescence; Figure S5. Immunostaining for phospho-eEF2 (p-eEF2, Thr56) and phospho-AS (p-ASyn, Ser129) in postmortem control hippocampus sections; Figure S6. Immunostaining for phospho-eEF2 (p-eEF2, Thr56) in postmortem PD hippocampus sections- Panoramic views; Figure S7. Immunostaining for phospho-eEF2 (p-eEF2, Thr56) and phospho-AS (p-ASyn, Ser129) in postmortem PD hippocampus sections; Figure S8. Effects of intramuscularly injected pre-formed fibrillar (PFF) AS on motor phenotype and survival of transgenic M83+/+ PD mice and Figure S9. Mitochondrial respiration and mitochondrial mass in differentiated N2A cells subsequent to eEF2K knockdown. (PDF 2444 kb).
- Published
- 2018
- Full Text
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