LIQUIDHOPE Advancing Liquid Biopsies for Neuroblastoma
LIQUIDHOPE Advancing Liquid Biopsies for Neuroblastoma
ERA-NET: TRANSCAN
Disciplines
Biology (10%); Computer Sciences (20%); Clinical Medicine (60%); Medical-Theoretical Sciences, Pharmacy (10%)
Keywords
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Oncology,
Diagnostics,
Biomarker,
Liquid Biopsy,
Neuroblastoma,
Precision Medicine
Das Neuroblastom ist für 11% aller durch Krebserkrankungen bedingten Todesfälle bei Kindern verantwortlich. Obwohl in den letzten Jahren große internationalen Anstrengungen unternommen wurden neue, verbesserte Therapien, z.B. Immuntherapien, zu implementieren, ist das Langzeitüberleben von PatientInnen mit metastasierender Hochrisikoerkrankung immer noch, mit einer Überlebensrate von weniger als 40% nach initialer Therapie und weniger als 10% nach einem Rezidiv, sehr schlecht. Liquid Biopsies spiegeln zu jedem Zeitpunkt während der Therapie und danach den genauen Krankheitsverlauf wider und haben daher das Potential Diagnostik und Behandlung von Kindern mit Hochrisiko-Neuroblastom zu revolutionieren. Da die Gewinnung von Blut- und Knochnmarksproben weniger invasiv als klassische Tumorbiopsien ist, sind diese eine hervorragende Quelle für Biomarker zur Verlaufskontrolle und als Grundlage für Therapieentscheidungen. Das LIQUIDHOPE- Konsortium bringt international anerkannte ExpertInnen auf den Gebieten der biologischen und computer- gestützten Forschung beim Neuroblastom mit führenden pädiatrischen OnkologInnen zusammen um einen Paradigmenwechsel in der onkologischen Diagnostik voranzutreiben. Das CCRI und andere Experten auf dem Gebiet haben beobachtet, dass bei mehr als 95% aller PatientInnen mit Hochrisiko-Neuroblastom, Tumorzellen ins Knochenmark metastasieren/disseminieren, wo einzelne Tumorzellen die initiale Chemotherapie überdauern können und oftmals zu einem Rezidiv führen. Wir konnten zeigen, dass PatientInnen, bei denen die initiale Chemotherapie nicht in der Lage war alle Tumorzellen aus dem Knochenmark zu eliminieren, deutlich schlechtere Überlebenschancen hatten. Genetische Analysen der zellfreien DNA aus Blut- und Knochenmarksplasma lieferten überdies wichtige zusätzliche Informationen. Wir gehen davon aus, dass die Implementierung der, von uns etablierten Methoden, zur Detektion und Biomarkercharakterisierung disseminierter Tumorzellen im Knochenmark und die Kombination mit Analysen der zellfreien DNA aus Blut und Knochenmark, die Abschätzung der Rezidivwahrscheinlichkeit erleichtern bzw. Verlaufskontrollen und eine präzisere Therapiewahl ermöglichen wird. Im Rahmen des LIQUIDHOPE Netzwerks, strebt das CCRI einen raschen Transfer von `Liquid Biopsy Verfahren in den klinischen Alltag an. Dies soll helfen die derzeitigen Probleme bei der Abschätzung des Therapieerfolgs, bei der Detektion von minimaler Resterkrankung und der Identifizierung von (immun)therapeutischen Angriffspunkten zu lösen. Wir planen, Tumormarker und immuntherapeutische Zielmoleküle auf disseminierten Tumorzellen in Knochenmarksproben, mithilfe eines automatisierten Mikroskopiesystems zu quantifizieren und mittels Digital Droplet-PCR DNA-Marker in Blut und Knochenmark zu analysieren. Diese Verfahren werden durch bioinformatische Analysen unterstützt, die auf neuesten Deep-learning-Algorithmen basieren sowie Software zur Visualisierung von komplexen multi-dimensionalen Daten. In einem Ringversuch sollen Spezifität und Sensitivität der von uns etablierten Biomarkertests gemeinsam mit denen der LIQUIDHOPE-Partner verglichen werden, um dann prospektiv im Rahmen der neuen Europa-weiten Hochrisiko-Neuroblastom Studie, SIOPEN-HR-NBL2, erhoben zu werden. Diese innovativen Liquid Biopsy Verfahren werden helfen, jene Kombinationen aus Blut- und Knochenmarksmarkern zu identifizieren und validieren, die eine Abschätzung des Therapieerfolgs, eine Verlaufskontrolle minimaler Resterkrankung und die Früherkennung von Rezidiven ermöglichen, und dadurch personalisierte Diagnostik und Behandlung von Kindern mit Neuroblastom wesentlich vorantreiben.
Neuroblastoma accounts for 11% of all cancer-related deaths in children. Despite considerable international efforts to improve treatment, including anti-GD2-directed immunotherapy, long- term survival of high-risk patients remains below 40% and below 10% for patients experiencing a relapse. Liquid biopsies, blood and bone marrow, have the power to revolutionize clinical care for children with high-risk neuroblastoma by reflecting precise disease status at any time during treatment and are a less invasive source of biomarkers for patient monitoring and therapeutic decision-making. The LIQUIDHOPE consortium brings together international experts in the fields of cancer research, bioinformatics and oncologists to shift the current paradigm in cancer diagnostics. CCRI and others have observed that at diagnosis >95% of patients with high-risk neuroblastoma have disseminated tumor cells in the bone marrow. Some of these cells can survive chemotherapy and lead to cancer relapse months or years later. Pilot studies had shown that the detection of disseminated tumor cells in the bone marrow along with the analysis of cell-free DNA in blood may improve outcome prediction, patient monitoring and secondary treatment selection. Within LIQIDHOPE, CCRI has quantified tumor markers and targets for immunotherapy on disseminated tumor cells in the bone marrow using an automated microscopy platform. Cell-free tumor DNA in blood was measured via digital droplet PCR and sequencing methods. These tests were supported by bioinformatics analysis, novel deep-learning algorithms and software for visualizing complex multi-dimensional data. First, we established guidelines for the collection, transport and storage of blood and bone marrow samples. This is of particular importance since in international clinical trials these materials are often shipped to specialized laboratories for analysis. Our study showed that a reduction of liquid biopsy markers correlated with the clinical therapy response. Specifically, patients, who do not show any tumor cells in the bone marrow or tumor markers in the cell- free DNA had better chances of survival. Cell-free DNA analysis was particularly well suited to detect relapse, in some cases several weeks before they were detected in the clinic. We also discovered that immunotherapy targets are not evenly present on tumor cells, which might explain, why current immunotherapies fail to eradicate all tumor cells and therefore fail to cure all patients. In conclusion, integrated liquid biopsy tests in blood and bone marrow allow a more precise therapy response evaluation, sensitive monitoring of minimal disease and early detection of relapse. Our guidelines and liquid biopsy tests are now used in the recently opened European clinical trial for high-risk neuroblastoma, SIOPEN/HR-NBL2, with the hope to improve diagnostics and treatment of children with neuroblastoma.
- Jo Vandesompele, Ghent University - Belgium
- Gudrun Schleiermacher, Institut Curie - France
- Hedwig Deubzer, Charité Universitätsmedizin Berlin - Germany
- Godelieve Andrea Maria Tytgat, Princess Maxima Center for Pediatric Oncology - Netherlands
- Jaime Font De Mora, Hospital Universitario La Fe - Spain
Research Output
- 282 Citations
- 12 Publications
- 6 Datasets & models
- 6 Scientific Awards
- 1 Fundings
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2021
Title Evaluation of Deep Learning Architectures for Complex Immunofluorescence Nuclear Image Segmentation DOI 10.1109/tmi.2021.3069558 Type Journal Article Author Kromp F Journal IEEE Transactions on Medical Imaging Pages 1934-1949 Link Publication -
2021
Title GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity DOI 10.1016/j.ccell.2021.12.005 Type Journal Article Author Heitzeneder S Journal Cancer Cell Link Publication -
2021
Title Landscape of Bone Marrow Metastasis in Human Neuroblastoma Unraveled by Transcriptomics and Deep Multiplex Imaging DOI 10.3390/cancers13174311 Type Journal Article Author Lazic D Journal Cancers Pages 4311 Link Publication -
2022
Title The evolutionary dynamics of extrachromosomal DNA in human cancers. DOI 10.25418/crick.21286530 Type Other Author Lange J -
2023
Title Single-cell transcriptomics and epigenomics unravel the role of monocytes in neuroblastoma bone marrow metastasis DOI 10.1038/s41467-023-39210-0 Type Journal Article Author Fetahu I Journal Nature Communications Pages 3620 Link Publication -
2022
Title The evolutionary dynamics of extrachromosomal DNA in human cancers DOI 10.1038/s41588-022-01177-x Type Journal Article Author Lange J Journal Nature Genetics Pages 1527-1533 Link Publication -
2022
Title Human repair-related Schwann cells adopt functions of antigen-presenting cells in vitro DOI 10.1101/2022.03.07.483322 Type Preprint Author Berner J Pages 2022.03.07.483322 Link Publication -
2022
Title Cross-species analysis identifies conserved transcriptional mechanisms of neutrophil maturation DOI 10.1101/2022.11.28.518146 Type Preprint Author Kirchberger S Pages 2022.11.28.518146 Link Publication -
2022
Title Human repair-related Schwann cells adopt functions of antigen-presenting cells in vitro DOI 10.1002/glia.24257 Type Journal Article Author Berner J Journal Glia Pages 2361-2377 Link Publication -
2024
Title Comparative transcriptomics coupled to developmental grading via transgenic zebrafish reporter strains identifies conserved features in neutrophil maturation DOI 10.1038/s41467-024-45802-1 Type Journal Article Author Kirchberger S Journal Nature Communications Pages 1792 Link Publication -
2020
Title Assessment of Pre-Analytical Sample Handling Conditions for Comprehensive Liquid Biopsy Analysis DOI 10.1016/j.jmoldx.2020.05.006 Type Journal Article Author Gerber T Journal The Journal of Molecular Diagnostics Pages 1070-1086 Link Publication -
2020
Title An annotated fluorescence image dataset for training nuclear segmentation methods. DOI 10.1038/s41597-020-00608-w Type Journal Article Author Bozsaky E Journal Scientific data Pages 262
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2021
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Title Landscape of Bone Marrow Metastasis in Human Neuroblastoma Unraveled by Transcriptomics and Deep Multiplex Imaging DOI 10.5281/zenodo.6621045 Type Database/Collection of data Public Access Link Link -
2021
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Title Landscape of Bone Marrow Metastasis in Human Neuroblastoma Unraveled by Transcriptomics and Deep Multiplex Imaging DOI 10.5281/zenodo.5906988 Type Database/Collection of data Public Access Link Link -
2021
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Title Landscape of Bone Marrow Metastasis in Human Neuroblastoma Unraveled by Transcriptomics and Deep Multiplex Imaging DOI 10.5281/zenodo.5906989 Type Database/Collection of data Public Access Link Link -
2020
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Title Metadata record for: An annotated fluorescence image dataset for training nuclear segmentation methods DOI 10.6084/m9.figshare.12570854 Type Database/Collection of data Public Access Link Link -
2020
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Title Metadata record for: An annotated fluorescence image dataset for training nuclear segmentation methods DOI 10.6084/m9.figshare.12570854.v1 Type Database/Collection of data Public Access Link Link -
2019
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Title Deep Learning architectures for generalized immunofluorescence based nuclear image segmentation DOI 10.48550/arxiv.1907.12975 Type Database/Collection of data Public Access Link Link
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2022
Title Member of the Executive Committee of the European Society of Pediatric Oncology Neuroblastoma (SIOPEN) Type Prestigious/honorary/advisory position to an external body Level of Recognition Continental/International -
2022
Title Talk at the Austrian Society for Cytology - Alpenflow Meeting, Bad Ischl, Austria Type Personally asked as a key note speaker to a conference Level of Recognition National (any country) -
2022
Title Talk at SIOPE Annual Meeting (online) Type Personally asked as a key note speaker to a conference Level of Recognition Continental/International -
2021
Title Talk at the Advances in Neuroblastoma Research (ANR) (online) Type Personally asked as a key note speaker to a conference Level of Recognition Continental/International -
2021
Title Talk at the 33rd European Congress of Pathology (online) Type Personally asked as a key note speaker to a conference Level of Recognition Continental/International -
2021
Title Talk at the SIOPE Annual Meeting (online) Type Personally asked as a key note speaker to a conference Level of Recognition Continental/International
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2022
Title MAPMET - Mapping metastatic cancer by multi-modal imaging Type Other Start of Funding 2022 Funder Austrian Science Fund (FWF)