Search

Your search keyword '"Waanders, Esme"' showing total 2 results
Start Over Author "Waanders, Esme" Topic cancer
2 results on '"Waanders, Esme"'

1. Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia

Author

Tzoneva, Gannie, Dieck, Chelsea L, Oshima, Koichi, Ambesi-Impiombato, Alberto, Sánchez-Martín, Marta, Madubata, Chioma J, Khiabanian, Hossein, Yu, Jiangyan, Waanders, Esme, Iacobucci, Ilaria, Sulis, Maria Luisa, Kato, Motohiro, Koh, Katsuyoshi, Paganin, Maddalena, Basso, Giuseppe, Gastier-Foster, Julie M, Loh, Mignon L, Kirschner-Schwabe, Renate, Mullighan, Charles G, Rabadan, Raul, and Ferrando, Adolfo A

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Hematology, Cancer, Childhood Leukemia, Genetics, Rare Diseases, Pediatric, Pediatric Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 5'-Nucleotidase, Animals, Cell Proliferation, Clonal Evolution, Disease Models, Animal, Drug Resistance, Neoplasm, Female, Gain of Function Mutation, Guanosine, HEK293 Cells, Humans, IMP Dehydrogenase, Male, Mercaptopurine, Mice, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Purines, Receptor, Notch1, Recurrence, Xenograft Model Antitumor Assays, General Science & Technology
Abstract

Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.

Published
2018

2. Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

Author

Langenberg, Karin P.S., Meister, Michael T., Bakhuizen, Jette J., Boer, Judith M., van Eijkelenburg, Natasha K.A., Hulleman, Esther, Ilan, Uri, Looze, Eleonora J., Dierselhuis, Miranda P., van der Lugt, Jasper, Breunis, Willemijn, Schild, Linda G., Ober, Kimberley, van Hooff, Sander R., Scheijde-Vermeulen, Marijn A., Hiemcke-Jiwa, Laura S., Flucke, Uta E., Kranendonk, Mariette E.G., Wesseling, Pieter, Sonneveld, Edwin, Punt, Simone, Boltjes, Arjan, van Dijk, Freerk, Verwiel, Eugene T.P., Volckmann, Richard, Hehir-Kwa, Jayne Y., Kester, Lennart A., Koudijs, Marco M.J., Waanders, Esme, Holstege, Frank C.P., Vormoor, H. Josef, Hoving, Eelco W., van Noesel, Max M., Pieters, Rob, Kool, Marcel, Stumpf, Miriam, Blattner-Johnson, Mirjam, Balasubramanian, Gnana P., Van Tilburg, Cornelis M., Jones, Barbara C., Jones, David T.W., Witt, Olaf, Pfister, Stefan M., Jongmans, Marjolijn C.J., Kuiper, Roland P., de Krijger, Ronald R., Wijnen, Marc H.W., den Boer, Monique L., Zwaan, C. Michel, Kemmeren, Patrick, Koster, Jan, Tops, Bastiaan B.J., Goemans, Bianca F., Molenaar, Jan J., Dep Scheikunde, Afd Pharmaceutics, Pharmaceutics, Dep Scheikunde, Afd Pharmaceutics, Pharmaceutics, Center of Experimental and Molecular Medicine, Oncogenomics, and CCA - Cancer Treatment and Quality of Life

Subjects
Cancer Research, Adolescent, Molecular biology, Precision medicine, High-Throughput Nucleotide Sequencing, Medical Oncology, Hereditary, Oncology, Neoplasms, Mutation, Exome Sequencing, Next-generation sequencing, Humans, Molecular targeted therapy, Prospective Studies, Child, Cancer
Abstract

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival.

Published
2022

Catalog

Books, media, physical & digital resources
See catalog results