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Open Access
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Article
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Feasibility of functional precision medicine for guiding treatment of relapsed or refractory pediatric cancers
In an observational study evaluating functional precision medicine in children and adolescents with relapsed or refractory solid and hematologic malignancies, it was feasible to provide personalized treatment recommendations to treating physicians on the basis of genomic profiling and ex vivo drug sensitivity testing within 4 weeks.
- Arlet M. Acanda De La Rocha
- , Noah E. Berlow
- & Diana J. Azzam
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Article |
Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors
An observational study reports the joint effects of polygenic risk scores and radiation treatment exposure with a subsequent increased risk of multiple solid cancers in two large cohorts of survivors of childhood cancer.
- Todd M. Gibson
- , Danielle M. Karyadi
- & Lindsay M. Morton
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Article
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The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial
In a phase 2 trial, the oral type II RAF inhibitor tovorafenib exhibited an overall response rate of 67% in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma.
- Lindsay B. Kilburn
- , Dong-Anh Khuong-Quang
- & Karsten Nysom
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Article
| Open Access
Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer
In a pooled analysis of six international studies involving about 17,900 female survivors of childhood cancer, the use of doxorubicin was associated with a dose-dependent risk of subsequent breast cancer, irrespective of prior chest radiotherapy exposure.
- Yuehan Wang
- , Cécile M. Ronckers
- & Jeanette F. Winther
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Article
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Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia
In children with relapsed or refractory B cell acute lymphoblastic leukemia and in complete remission after CD19 CAR-T cell therapy, long-lived CAR-T cells express a persistence gene signature that is also present in persistent CD19 CAR-T cells from adults with chronic lymphocytic leukemia.
- Nathaniel D. Anderson
- , Jack Birch
- & Sara Ghorashian
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Consensus Statement |
A joint international consensus statement for measuring quality of survival for patients with childhood cancer
The International Childhood Cancer Outcome Project group, involving survivors and other relevant stakeholders, develop a set of core outcomes to measure the quality of care for 17 types of childhood cancers.
- Rebecca J. van Kalsbeek
- , Melissa M. Hudson
- & Lisa Zwiers
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Article |
Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results
In updated results from a phase 1 trial of GD2-specific CAR-NKT cells in patients with neuroblastoma, no dose-limiting toxicities were observed across multiple dose levels; the maximum tolerated dose was not reached; and there was evidence of anti-tumor activity.
- Andras Heczey
- , Xin Xu
- & Leonid S. Metelitsa
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Article
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Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results
In children, adolescents and adults with mutated ALK-driven relapsed or refractory neuroblastoma, a third-generation ALK inhibitor with or without chemotherapy was well tolerated, and recommended phase 2 doses were successfully identified in all patient groups.
- Kelly C. Goldsmith
- , Julie R. Park
- & Yael P. Mossé
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News & Views |
Accurate diagnosis of pediatric brain cancers
Integrative approaches continue to improve diagnostic accuracy for pediatric brain cancers, but much more is needed from researchers, governments and regulators if precision medicine with curative treatments are to become a reality.
- Pratiti Bandopadhayay
- & Elaine R. Mardis
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Article
| Open Access
Diagnostic classification of childhood cancer using multiscale transcriptomics
A new multilevel clustering approach applied retrospectively to 13,000 transcriptomes of different tumors reveals a new diagnostic classification of childhood cancers, in some cases allowing a better prediction of disease outcomes.
- Federico Comitani
- , Joshua O. Nash
- & Adam Shlien
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Article
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Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology
The integration of DNA methylation profiling and targeted sequencing with neuropathology improves the diagnostic accuracy of central nervous system tumors in a population-based cohort of more than 1,200 newly diagnosed pediatric patients.
- Dominik Sturm
- , David Capper
- & David. T. W. Jones
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Article
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Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response
Pharmacotyping analyses of large cohorts of pediatric acute lymphoblastic leukemia identify correlations between drug sensitivities and clinical outcomes across different genomic subtypes.
- Shawn H. R. Lee
- , Wenjian Yang
- & Jun J. Yang
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News & Views |
Predicting chronic morbidity in childhood cancer survivors
Incorporating genetic factors into risk models improves the prediction of severe obesity for survivors of childhood cancer, which could promote early interventions and better long-term care.
- Lynda M. Vrooman
- & Lisa R. Diller
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Article |
Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer
An interim report from the GAIN/iCat2 study shows that molecular profiling of pediatric solid malignancies clarifies diagnostic classifications and provides opportunities for matched targeted therapy.
- Alanna J. Church
- , Laura B. Corson
- & Katherine A. Janeway
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World View |
How to correct the market for children’s cancer drugs
The development of pediatric cancer drugs is vastly underfunded compared with that for adults, but legislation can correct market failures.
- Nancy F. Goodman
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Article |
Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication
The combination of anti-GD2 and CD47 blockade mediates robust anti-tumor activity in mouse models of neuroblastoma, osteosarcoma and small-cell lung cancer by reorienting macrophage activity toward tumor cell phagocytosis.
- Johanna Theruvath
- , Marie Menard
- & Robbie G. Majzner
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Article
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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.
- Anirban Das
- , Sumedha Sudhaman
- & Uri Tabori
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Article
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CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial
Bicistronic CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in pediatric and young adult patients with B cell acute lymphoblastic leukemia, with relapses associated with limited CAR T cell persistence.
- Shaun Cordoba
- , Shimobi Onuoha
- & Persis J. Amrolia
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Article |
Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis
In an interim analysis of a phase 1 trial, repeated intracranial infusions of HER2-specific CAR T cells were well tolerated with no observed dose-limiting toxicities in three young adult patients with CNS tumors.
- Nicholas A. Vitanza
- , Adam J. Johnson
- & Julie R. Park
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Article |
Cabozantinib for neurofibromatosis type 1–related plexiform neurofibromas: a phase 2 trial
Cabozantinib, an inhibitor of multiple receptor tyrosine kinases, has efficacy in a mouse model of neurofibromatosis type I and has clinical activity in reducing plexiform neurofibroma volume in a phase II trial of patients with NF1.
- Michael J. Fisher
- , Chie-Schin Shih
- & D. Wade Clapp
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News & Views |
Entering the era of precision medicine in pediatric oncology
The Zero Childhood Cancer Program’s multi-platform sequencing approach identified molecular alterations in 94% of a cohort of 247 pediatric patients with high-risk cancers, which has enabled more-precise diagnoses and alternative therapeutic recommendations.
- Djihad Hadjadj
- , Shriya Deshmukh
- & Nada Jabado
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Brief Communication |
Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis
In an interim analysis of a first-in-human phase 1 trial of patients with neuroblastoma, highly pure GD2-specific CAR-NKT cells were well tolerated with no observed dose-limiting toxicities.
- Andras Heczey
- , Amy N. Courtney
- & Leonid S. Metelitsa
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Article |
Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer
The Zero Childhood Cancer pediatric precision medicine program informs treatment recommendations for children with high-risk cancers through comprehensive molecular profiling
- Marie Wong
- , Chelsea Mayoh
- & Mark J. Cowley
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Article |
Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma
Intraventricularly delivered monovalent and trivalent CAR T cells exhibit greater therapeutic efficacy as compared with intravenously delivered CAR T cells in medulloblastoma xenograft mouse models and show potency in ependymoma xenograft mouse models.
- Laura K. Donovan
- , Alberto Delaidelli
- & Michael D. Taylor
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Letter |
Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors
CAR T cells administered intracerebroventricularly or intratumorally exhibit more rapid kinetics, reduced systemic toxicity and greater therapeutic potency as compared to intravenously delivered CAR T cells in atypical teratoid/rhabdoid tumor xenograft mouse models.
- Johanna Theruvath
- , Elena Sotillo
- & Crystal L. Mackall
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Review Article |
Developmental origins and emerging therapeutic opportunities for childhood cancer
Childhood cancers are developmentally distinct from adult cancers and arise from cellular reprogramming as a result of epigenetic mutations or gene fusions, providing unique therapeutic opportunities.
- Mariella Filbin
- & Michelle Monje
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Resource |
A biobank of patient-derived pediatric brain tumor models
A resource of preclinical pediatric brain tumor models with detailed molecular characterization provides a platform for the community to test novel therapeutic approaches.
- Sebastian Brabetz
- , Sarah E. S. Leary
- & James M. Olson
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Article |
Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells
Genomic and functional analysis of intratumor heterogeneity in pediatric glioma uncovers early clonal divergence and stable spontaneous cooperation between subclonal populations throughout tumor evolution.
- Mara Vinci
- , Anna Burford
- & Chris Jones
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News & Views |
CAR T cells for childhood diffuse midline gliomas
Anti-GD2 chimeric antigen receptor (CAR)-modified T cells may be a new and innovative approach for the treatment of pediatric H3-K27M-mutant diffuse midline gliomas.
- Vijay Ramaswamy
- & Michael D Taylor
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News & Views |
Genomics in childhood acute myeloid leukemia comes of age
A Children's Oncology Group study of nearly 1,000 pediatric acute myeloid leukemia (AML) cases reveals marked differences between the genomic landscapes of pediatric and adult AML and offers directions for future work.
- Andrew M Brunner
- & Timothy A Graubert
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Resource |
The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions
A comprehensive molecular analysis of almost 1,000 pediatric subjects with acute myeloid leukemia (AML) uncovers widespread differences in pediatric AML as compared to adult AML, including a higher frequency of structural variants and different mutational patterns and epigenetic signatures. Future studies are needed to characterize the functional relevance of these alterations and to explore age-tailored therapies to improve disease control in younger patients.
- Hamid Bolouri
- , Jason E Farrar
- & Soheil Meshinchi
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Editorial |
Children first
Drugs administered to children with cancer were typically developed under the assumption that childhood cancers are similar to their tissue-matched adult counterparts. Focusing on identifying and targeting alterations present specifically in childhood tumors will accelerate the development of tailored therapies and improve the prognosis of children with cancer.
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Resource |
DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma
DNA methylation sequencing and bioinformatic analyses uncover an epigenetic disease spectrum in Ewing sarcoma. These characteristic epigenome patterns correlate with state of differentiation and disease aggressiveness, and pave the way for the development of biomarkers.
- Nathan C Sheffield
- , Gaelle Pierron
- & Eleni M Tomazou
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News & Views |
Hunting ALK to feed targeted cancer therapy
Neuroblastoma is a fatal childhood cancer, but lack of knowledge about the underlying causative genes has hampered the development of effective therapies. The identification of anaplastic lymphoma kinase (ALK) mutations as drivers of neuroblastoma has indicated that targeted therapy with ALK inhibitors might be a valuable strategy in the fight against this lethal cancer.
- Anton Wellstein
- & Jeffrey A Toretsky
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News & Views |
Crippling SWI-SNF makes tumors GLI-ful
The chromatin remodeling complex SWI-SNF is altered in cancer. New findings now show that the core component SNF5 can block a Hedgehog (Hh) effector, which promotes malignant rhabdoid tumor growth when SNF5 is lost (pages 1429–1433). Targeting this Hh effector may be a way to combat these aggressive childhood tumors.
- Jeremy F Reiter
Precision-guided treatment in high-risk pediatric cancers
The search for child cancer drugs grows up