@article{e0b0c30c765c428da04f53a8e63b8a06,
title = "Functional precision medicine identifies new therapeutic candidates for medulloblastoma",
abstract = "Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients{\textquoteright} tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. Significance: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.",
author = "Rusert, {Jessica M.} and Juarez, {Edwin F.} and Sebastian Brabetz and James Jensen and Alexandra Garancher and Chau, {Lianne Q.} and Tacheva-Grigorova, {Silvia K.} and Sameerah Wahab and Udaka, {Yoko T.} and Darren Finlay and Huriye Seker-Cin and Brendan Reardon and Susanne Grobner and Jonathan Serrano and Jonas Ecker and Lin Qi and Mari Kogiso and Yuchen Du and Baxter, {Patricia A.} and Henderson, {Jacob J.} and Berens, {Michael E.} and Kristiina Vuori and Till Milde and Cho, {Yoon Jae} and Li, {Xiao Nan} and Olson, {James M.} and Iris Reyes and Matija Snuderl and Wong, {Terence C.} and Dimmock, {David P.} and Nahas, {Shareef A.} and Denise Malicki and Crawford, {John R.} and Levy, {Michael L.} and {van Allen}, {Eliezer M.} and Pfister, {Stefan M.} and Pablo Tamayo and Marcel Kool and Mesirov, {Jill P.} and Wechsler-Reya, {Robert J.}",
note = "Funding Information: The authors gratefully acknowledge the Animal Facilities at UCSD and SBP for help with animal care and husbandry. We would also like to acknowledge the DKFZ Genomics and Proteomics Core Facility, DKFZ Heidelberg, Germany, and the AMC Department of Oncogenomics, Amsterdam, the Netherlands, for performing high-throughput sequencing and microarray analyses to a very high standard. We also thank the DKFZ data management group for their excellent support in processing the sequencing data. We are also indebted to the Conrad Prebys Center for Chemical Genomics, including Fu-Yue Zeng, Luis Orozco, and Michael Jackson, for their help with drug library selection and plating compounds and Sumeet Salaniwal for assistance with bioinformatics. We are most appreciative of Anthony Pinkerton and Robert Ardecky for their advice on in vivo drug testing. We gratefully acknowledge Brian James of the Genomics-DNA Analysis core at SBP for his help with PDX fingerprinting. This work was supported by funding from the NCI (2R01 CA159859 to R.J. Wechsler-Reya; P30 CA30199 to R.J. Wechsler-Reya; U01CA184898 to J.P. Mesirov; U24CA194107 to J.P. Mesirov; U24CA220341 to J.P. Mesirov and P. Tamayo; U01CA217885 to J.P. Mesirov and P. Tamayo); the National Institute for Neurological Disorders and Stroke (R01 NS096368 to R.J. Wechsler-Reya); the National Institute of General Medical Sciences (R01GM074024 to J.P. Mesirv), Deutsche Krebshilfe (111537 to M. Kool and S.M. Pfister), BMBF (01KT1605 to S.M. Pfister), and the Helmholtz International Graduate School for Cancer Research (to S. Brabetz). SBP{\textquoteright}s Shared Resources are supported by SBP{\textquoteright}s NCI Cancer Center Support Grant P30 CA030199. Methylation profiling at NYU was supported in part by a grant from the Friedeberg Charitable Foundation (to M. Snuderl). Work in R.J. Wechsler-Reya{\textquoteright}s laboratory was also funded by the Pediatric Brain Tumor Foundation, Accelerate Brain Cancer Cure, Ian{\textquoteright}s Friends Foundation, Alex{\textquoteright}s Lemonade Stand Foundation, William{\textquoteright}s Superhero Fund, the McDowell Charity Trust, and the California Institute for Regenerative Medicine. Funding Information: S.K. Tacheva-Grigorova reports other compensation from Allogene Therapeutics and Pfizer outside the submitted work. D. Finlay reports grants from NIH/ NCI during the conduct of the study and grants from NIH/NCI outside the submitted work. M. Snuderl reports personal fees from Illumina, Inc. outside the submitted work. D.P. Dimmock reports personal fees from Biomarin, Audentes, Ichorion, and Complete Genomics outside the submitted work; in addition, D.P. Dimmock has a patent for US8718950B2 licensed to HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY. E.M. Van Allen reports personal fees from Tango Therapeutics, Genome Medical, Invitae, Monte Rosa Therapeutics, Manifold Bio, Illumina, and Enara Bio, and grants from Novartis and BMS outside the submitted work. S.M. Pfister reports grants from IMI-2 Grant during the conduct of the study. M. Kool reports grants from Deutsche Krebshilfe during the conduct of the study. R.J. Wechsler-Reya reports grants from NCI, National Institute of Neurological Disorders and Stroke, Pediatric Brain Tumor Foundation, Accelerate Brain Cancer Cure, Ian{\textquoteright}s Friends Foundation, Alex{\textquoteright}s Lemonade Stand Foundation, William{\textquoteright}s Superhero Fund, McDowell Charity Trust, and California Institute for Regenerative Medicine during the conduct of the study. Outside the submitted work, R.J. Wechsler-Reya serves as Director of the Clayes Center for Neuro-Oncology and Genomics at Rady Children{\textquoteright}s Institute for Genomic Medicine and receives personal fees for this service. No potential conflicts of interest were disclosed by the other authors. Funding Information: The authors gratefully acknowledge the Animal Facilities at UCSD and SBP for help with animal care and husbandry. We would also like to acknowledge the DKFZ Genomics and Proteomics Core Facility, DKFZ Heidelberg, Germany, and the AMC Department of Oncogenomics, Amsterdam, the Netherlands, for performing high-throughput sequencing and microarray analyses to a very high standard. We also thank the DKFZ data management group for their excellent support in processing the sequencing data. We are also indebted to the Conrad Prebys Center for Chemical Genomics, including Fu-Yue Zeng, Luis Orozco, and Michael Jackson, for their help with drug library selection and plating compounds and Sumeet Salaniwal for assistance with bioinformatics. We are most appreciative of Anthony Pinkerton and Robert Ardecky for their advice on in vivo drug testing. We gratefully acknowledge Brian James of the Genomics-DNA Analysis core at SBP for his help with PDX fingerprinting. This work was supported by funding from the NCI (2R01 CA159859 to R.J. Wechsler-Reya; P30 CA30199 to R.J. Wechsler-Reya; U01CA184898 to J.P. Mesirov; U24CA194107 to J.P. Mesirov; U24CA220341 to J.P. Mesirov and P. Tamayo; U01CA217885 to J.P. Mesirov and P. Tamayo); the National Institute for Neurological Disorders and Stroke (R01 NS096368 to R.J. Wechsler-Reya); the National Institute of General Medical Sciences (R01GM074024 to J.P. Mesirv), Deutsche Krebshilfe (111537 to M. Kool and S.M. Pfister), BMBF (01KT1605 to S.M. Pfister), and the Helmholtz International Graduate School for Cancer Research (to S. Brabetz). SBP?s Shared Resources are supported by SBP?s NCI Cancer Center Support Grant P30 CA030199. Methylation profiling at NYU was supported in part by a grant from the Friedeberg Charitable Foundation (to M. Snuderl). Work in R.J. Wechsler-Reya?s laboratory was also funded by the Pediatric Brain Tumor Foundation, Accelerate Brain Cancer Cure, Ian?s Friends Foundation, Alex?s Lemonade Stand Foundation, William?s Superhero Fund, the McDowell Charity Trust, and the California Institute for Regenerative Medicine. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = dec,
day = "1",
doi = "10.1158/0008-5472.CAN-20-1655",
language = "English (US)",
volume = "80",
pages = "5393--5407",
journal = "Cancer Research",
issn = "0008-5472",
number = "23",
}