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Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma.
Eur J Cancer. 2020 Sep; 136:52-68.EJ

Abstract

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy.

Authors+Show Affiliations

Paediatric Haematology & Oncology Division, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Electronic address: lucas.moreno@vhebron.net.Department of Paediatric Oncology, Great Ormond Street Hospital for Children, London, UK.Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA.Princess Máxima Centre for Paediatric Oncology, Utrecht, The Netherlands.Experimental Pediatric Oncology, University Children's Hospital, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.Department of Pediatric Oncology & Hematology, Charité University Hospital, Berlin, Germany.Department of Pediatric Oncology & Hematology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK Berlin), Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany.SIREDO, Department of Paediatric, Adolescents and Young Adults Oncology and INSERM U830, Institut Curie, Paris, France.Center for Medical Genetics Ghent (CMGG), Department of Biomolecular Medicine, Cancer Research Institute Ghent (CRIG), Belgium.Paediatric Drug Development, Children & Young People's Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, University Paris-Saclay & Inserm U1015, Villejuif, France.Division of Oncology, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania, USA; Perelman School of Medicine, University of Pennsylvania, USA.Department of Paediatrics, Medical Biophysics and Laboratory Medicine & Pathobiology, The Hospital for Sick Kids, Toronto, Canada.Solving Kids' Cancer, UK and National Cancer Research Institute Children's Cancer & Leukaemia Clinical Studies Group, UK.Neuroblastoma UK & Department of Physiology, Development & Neuroscience, University of Cambridge, UK.Pfizer Ltd, Surrey, UK.Hoffmann-La Roche Ltd, Basel, Switzerland.Cyclacel Limited, Dundee, UK.Center for Medical Genetics Ghent (CMGG), Department of Biomolecular Medicine, Cancer Research Institute Ghent (CRIG), Belgium.Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.Department of Translational Research, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.Department of Biochemistry and Molecular Biology, University of Wuerzburg, Germany.Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA.Paediatric Drug Development, Children & Young People's Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.Pediatric Oncology Department, University Hospital Brno, School of Medicine Masaryk University Brno, Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, ICRC Brno, St Anna University Hospital Brno, Czech Republic.Division of Oncology, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania, USA; Perelman School of Medicine, University of Pennsylvania, USA.Paediatric Drug Development, Children & Young People's Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.Astrazeneca, Early Clinical Projects, Oncology Translation Medicines Unit, Innovative Medicines Unit, Cambridge, UK.Astrazeneca, Early Clinical Projects, Oncology Translation Medicines Unit, Innovative Medicines Unit, Cambridge, UK.Department of Paediatric Haemaology/Oncology, Our Lady's Children's Hospital, Dublin, Ireland.Department of Oncology, University of Cambridge, UK.Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA.Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, University Paris-Saclay & Inserm U1015, Villejuif, France.Department of Clinical Research, Gustave Roussy, Paris-Sud University, Paris, France.Department of Pediatrics, University of Washington School of Medicine and Center for Clinical and Translational Research, Seattle Children's Hospital, USA.Paediatric Drug Development, Children & Young People's Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK; Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

32653773

Citation

Moreno, Lucas, et al. "Accelerating Drug Development for Neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy Forum From Innovative Therapies for Children With Cancer and International Society of Paediatric Oncology Europe Neuroblastoma." European Journal of Cancer (Oxford, England : 1990), vol. 136, 2020, pp. 52-68.
Moreno L, Barone G, DuBois SG, et al. Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma. Eur J Cancer. 2020;136:52-68.
Moreno, L., Barone, G., DuBois, S. G., Molenaar, J., Fischer, M., Schulte, J., Eggert, A., Schleiermacher, G., Speleman, F., Chesler, L., Geoerger, B., Hogarty, M. D., Irwin, M. S., Bird, N., Blanchard, G. B., Buckland, S., Caron, H., Davis, S., De Wilde, B., ... Pearson, A. D. J. (2020). Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma. European Journal of Cancer (Oxford, England : 1990), 136, 52-68. https://doi.org/10.1016/j.ejca.2020.05.010
Moreno L, et al. Accelerating Drug Development for Neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy Forum From Innovative Therapies for Children With Cancer and International Society of Paediatric Oncology Europe Neuroblastoma. Eur J Cancer. 2020;136:52-68. PubMed PMID: 32653773.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma. AU - Moreno,Lucas, AU - Barone,Giuseppe, AU - DuBois,Steven G, AU - Molenaar,Jan, AU - Fischer,Matthias, AU - Schulte,Johannes, AU - Eggert,Angelika, AU - Schleiermacher,Gudrun, AU - Speleman,Frank, AU - Chesler,Louis, AU - Geoerger,Birgit, AU - Hogarty,Michael D, AU - Irwin,Meredith S, AU - Bird,Nick, AU - Blanchard,Guy B, AU - Buckland,Sean, AU - Caron,Hubert, AU - Davis,Susan, AU - De Wilde,Bram, AU - Deubzer,Hedwig E, AU - Dolman,Emmy, AU - Eilers,Martin, AU - George,Rani E, AU - George,Sally, AU - Jaroslav,Štěrba, AU - Maris,John M, AU - Marshall,Lynley, AU - Merchant,Melinda, AU - Mortimer,Peter, AU - Owens,Cormac, AU - Philpott,Anna, AU - Poon,Evon, AU - Shay,Jerry W, AU - Tonelli,Roberto, AU - Valteau-Couanet,Dominique, AU - Vassal,Gilles, AU - Park,Julie R, AU - Pearson,Andrew D J, Y1 - 2020/07/09/ PY - 2020/01/09/received PY - 2020/04/16/revised PY - 2020/05/12/accepted PY - 2020/7/13/pubmed PY - 2020/7/13/medline PY - 2020/7/13/entrez KW - Clinical trials KW - Drug development KW - Epigenetics KW - MYCN KW - Neuroblastoma KW - Phase I KW - Preclinical testing SP - 52 EP - 68 JF - European journal of cancer (Oxford, England : 1990) JO - Eur. J. Cancer VL - 136 N2 - Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy. SN - 1879-0852 UR - https://www.unboundmedicine.com/medline/citation/32653773/Accelerating_drug_development_for_neuroblastoma:_Summary_of_the_Second_Neuroblastoma_Drug_Development_Strategy_forum_from_Innovative_Therapies_for_Children_with_Cancer_and_International_Society_of_Paediatric_Oncology_Europe_Neuroblastoma L2 - https://linkinghub.elsevier.com/retrieve/pii/S0959-8049(20)30276-8 DB - PRIME DP - Unbound Medicine ER -
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