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Prediction of DNA methylation-based tumor types from histopathology in central nervous system tumors with deep learning
A deep learning model is used to classify central nervous system tumors based on their DNA methylation profile directly from histopathology, and showed high accuracy in a large set of external validation cohorts, potentially informing downstream treatment.
- Danh-Tai Hoang
- , Eldad D. Shulman
- & Kenneth Aldape
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Article
| Open Access
Pemigatinib in previously treated solid tumors with activating FGFR1–FGFR3 alterations: phase 2 FIGHT-207 basket trial
In a tumor-agnostic phase 2 basket trial, the oral FGFR1–FGFR3 inhibitor pemigatinib elicits responses in tumor types beyond cholangiocarcinoma and bladder cancer and in tumor types with rarer FGFR alterations, with insights provided into resistance mechanisms.
- Jordi Rodón
- , Silvia Damian
- & Lipika Goyal
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Article |
Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results
In an interim analysis of an ongoing phase 1 trial of CAR T cells targeting EGFR and IL13Ra2 in patients with multifocal, recurrent glioblastoma, intrathecal delivery is feasible and well tolerated, with some reductions seen in tumor size.
- Stephen J. Bagley
- , Meghan Logun
- & Donald M. O’Rourke
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Article
| Open Access
Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial
In a large trial of patients with recurrent high-grade gliomas, IL-13Rα2-targeting CAR-T cells were feasible to manufacture and well tolerated when delivered via intratumoral and/or intraventricular routes.
- Christine E. Brown
- , Jonathan C. Hibbard
- & Behnam Badie
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Research Briefing |
Meningioma risk stratification with a targeted gene-expression biomarker
A validated biomarker risk score based on the expression of 34 genes improves risk stratification of patients with meningioma, including prediction of post-operative radiotherapy benefit.
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Article |
Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses
A risk score based on a 34-gene signature for outcome prediction in meningioma was developed and validated in large multi-institutional cohorts and showed better performance in discriminating postoperative menignioma outcomes compared with existing meningioma classification systems.
- William C. Chen
- , Abrar Choudhury
- & David R. Raleigh
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Correspondence |
BrainStorm: a multicenter international study to tackle CNS metastases in solid tumors
- Diogo Martins-Branco
- , Guilherme Nader-Marta
- & Nuria Kotecki
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Article
| Open Access
A H3K27M-targeted vaccine in adults with diffuse midline glioma
In this compassionate use study, treatment of adult patients with H3K27M-mutant diffuse midline glioma with a long peptide vaccine targeting H3K27M led to vaccine-induced peripheral T cell immune responses and encouraging clinical efficacy in the majority of patients, including a durable complete response.
- Niklas Grassl
- , Isabel Poschke
- & Katharina Sahm
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Comment |
Correcting the drug development paradigm for glioblastoma requires serial tissue sampling
A breakthrough in drug discovery for glioblastoma requires serial collection of tissue from the central nervous system via window of opportunity trials
- Kirit Singh
- , Kelly M. Hotchkiss
- & Mustafa Khasraw
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Research Highlight |
A new targeted therapy for low-grade glioma
The dual IDH1–IDH2 inhibitor vorasidenib more than doubled time to progression (relative to placebo) and thus represents the first new treatment in decades for patients with glioma.
- Karen O’Leary
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Article |
Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results
In a phase 2 trial of patients with untreated, recurrent and progressive brain metastases treated with an anti-programmed cell death protein 1 inhibitor, the overall intracranial benefit rate was 42.1%, which met the prespecified primary endpoint.
- Priscilla K. Brastianos
- , Albert E. Kim
- & Ryan J. Sullivan
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News & Views |
Advancing combination therapy for recurrent glioblastoma
Adding an oncolytic virus to classic immune checkpoint inhibition elicits treatment responses and survival benefit for select immunologically ‘cold’ recurrent glioblastomas, although creative treatment strategies are still needed for patients with highly anti-inflammatory tumors.
- Adela Wu
- & Michael Lim
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Article
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Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial
A safety and efficacy trial of a single intratumoral dose of the oncolytic adenovirus DNX-2401 followed by intravenous anti-PD-1 pembrolizumab in patients with recurrent glioblastoma shows an encouraging clinical benefit rate and 12 months overall survival.
- Farshad Nassiri
- , Vikas Patil
- & Gelareh Zadeh
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Research Briefing |
Using AI to improve the molecular classification of brain tumors
We used deep neural networks trained on optical histology and open-source genomic data to predict the molecular genetics of brain tumors during surgery. Our results represent how AI-based diagnostics can provide a valuable adjunct to wet laboratory methods for molecular testing in patients with cancer.
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Perspective |
Tumor inflammation-associated neurotoxicity
The authors describe a localized toxicity syndrome that is associated with immunotherapy treatment for CNS tumors and propose a new grading scale—with the goal of promoting research and standardizing both reporting and management.
- Jasia Mahdi
- , Jorg Dietrich
- & Michelle Monje
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Article
| Open Access
Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results
In an interim analysis of a phase 1 trial of concurrent intrathecal and intravenous anti-PD1 delivery in patients with leptomeningeal disease and melanoma, treatment was feasible and well-tolerated with no dose-limiting toxicities.
- Isabella C. Glitza Oliva
- , Sherise D. Ferguson
- & Michael A. Davies
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Brief Communication |
Artificial-intelligence-based molecular classification of diffuse gliomas using rapid, label-free optical imaging
DeepGlioma, a multimodal deep learning approach for intraoperative diagnostic screening of diffuse glioma, trained on stimulated Raman histology and large-scale public genomic data, can predict molecular alterations for diffuse glioma diagnosis with high accuracy.
- Todd Hollon
- , Cheng Jiang
- & Daniel A. Orringer
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Article
| Open Access
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
| Open Access
Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial
The dual IDH1/IDH2 inhibitor vorasidenib exhibited better brain permeability and target engagement than ivosidenib in a pilot perioperative randomized clinical trial in patients with IDH1-mutant glioma.
- Ingo K. Mellinghoff
- , Min Lu
- & Timothy F. Cloughesy
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Article
| Open Access
Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial
Findings from the TUXEDO-1 trial demonstrate efficacy of the antibody–drug conjugate trastuzumab deruxtecan for treatment of brain metastases in patients with HER2-positive breast cancer.
- Rupert Bartsch
- , Anna Sophie Berghoff
- & Matthias Preusser
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Article
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Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial
Results from a pivotal single-arm phase 2 trial show that the repeated intratumoral administration of the oncolytic herpes virus G47∆ in residual or recurrent glioblastoma exhibits survival benefit and a safe profile.
- Tomoki Todo
- , Hirotaka Ito
- & Minoru Tanaka
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Research Briefing |
Towards personalizing radiotherapy for brain metastasis
Secretion of S100A9 by brain metastatic cells activates radioresistance. Blood S100A9 could be used as a biomarker to predict responses to irradiation and to guide a combination therapy with a radiosensitizer.
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Article
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Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism
A comprehensive analysis of models of brain metastasis and multiple cohorts of patient samples identifies a targetable molecular mechanism underlying the resistance to whole-brain radiotherapy that can inform patient selection for personalized radiotherapy.
- Cátia Monteiro
- , Lauritz Miarka
- & Manuel Valiente
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Article
| Open Access
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 |
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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Letter |
Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis
In a phase 2 clinical trial cohort of patients with leptomeningeal disease, anti-PD-1 monotherapy was safe and associated with a 3-month overall survival of 60%.
- Priscilla K. Brastianos
- , Eudocia Quant Lee
- & Ryan J. Sullivan
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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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Article |
Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma
Neoadjuvant pembrolizumab promotes a survival benefit with intratumoral and systemic immune responses in patients with recurrent glioblastoma.
- Timothy F. Cloughesy
- , Aaron Y. Mochizuki
- & Robert M. Prins
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Resource |
The molecular landscape of glioma in patients with Neurofibromatosis 1
An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.
- Fulvio D’Angelo
- , Michele Ceccarelli
- & Antonio Iavarone
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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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Letter |
BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors
In pediatric brain tumors that are accompanied by epileptic seizures, the BRAF somatic mutation V600E contributes to intrinsic epileptic properties in neurons, which can be suppressed by vemurafenib in mice.
- Hyun Yong Koh
- , Se Hoon Kim
- & Jeong Ho Lee
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Resource |
The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space
In-depth methylation analysis of formalin-fixed paraffin-embedded glioblastoma samples demonstrates heterogeneity between primary and recurring tumors and enables prediction of composition of the tumor microenvironment and insights into progression.
- Johanna Klughammer
- , Barbara Kiesel
- & Christoph Bock
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Article |
Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors
Patients with glioblastoma experience lymphopenia and sequestration of T cells in the bone marrow, which is recapitulated in mice with brain tumors, where the reversible nature of this effect is demonstrated by an approach that enables the efficacy of other immunotherapeutics.
- Pakawat Chongsathidkiet
- , Christina Jackson
- & Peter E. Fecci
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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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Article |
Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma
Combined inhibition of oncogene-driven glucose uptake and induction of cytoplasmic-p53 activity induces apoptosis in a subset of glioblastoma samples. In mice, PET imaging of glucose uptake predicts glioblastoma response to this combination therapy.
- Wilson X Mai
- , Laura Gosa
- & David A Nathanson
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Article |
A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors
Simultaneous activation of Wnt and Shh pathways in murine neural precursor cells results in the formation of embryonal tumors with multilayered rosettes (ETMR) that recapitulate the histological and molecular features of human tumors. This novel mouse model represents a platform for evaluating therapeutic approaches for this rare malignant pediatric brain tumor, and provides novel insights into the cell of origin and molecular mechanisms driving the disease.
- Julia E Neumann
- , Annika K Wefers
- & Ulrich Schüller
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Article |
Gpr124 is essential for blood–brain barrier integrity in central nervous system disease
The G-protein-coupled receptor GPR124, acting through the canonical Wnt pathway, is required for the maintenance of blood–brain barrier function in mouse models of stroke and glioblastoma.
- Junlei Chang
- , Michael R Mancuso
- & Calvin J Kuo
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Article |
EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas
Although mutant H3K27M histones inhibit PRC2 in diffuse intrinsic pontine gliomas, these tumors exhibit significant amounts of PRC2 activity. The repression of several genes, including INK4A, by residual EZH2 activity is required for tumor growth, and EZH2 inhibitors therefore represent potential therapies for these patients.
- Faizaan Mohammad
- , Simon Weissmann
- & Kristian Helin
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Letter |
Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas
Nucleosomes containing mutant K27M histones in diffuse intrinsic pediatric gliomas (DIPG) exclude PRC2 binding and recruit BET bromodomain proteins; however, residual PRC2-dependent repression of specific loci, is required for DIPG oncogenesis. These results provide a rationale for targeting these epigenetic regulators in patients.
- Andrea Piunti
- , Rintaro Hashizume
- & Ali Shilatifard
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Letter |
Recurrent MET fusion genes represent a drug target in pediatric glioblastoma
Whole-genome sequencing identified recurrent fusions involving the MET oncogene, and MET inhibitors suppressed tumor growth in mouse models and in a human patient.
- Sebastian Bender
- , Jan Gronych
- & David T W Jones
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Brief Communication |
Functionally defined therapeutic targets in diffuse intrinsic pontine glioma
The study describes the use of integrative approaches to search for candidate therapeutic targets for DIPG, and the identification of an HDAC inhibitor as a potential treatment strategy
- Catherine S Grasso
- , Yujie Tang
- & Michelle Monje
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Article |
The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog−driven medulloblastoma
Deficiency in Gnas, encoding the Gs protein α subunit, is sufficient to induce medulloblastoma in mice due to derepression of the Sonic hedgehog pathway.
- Xuelian He
- , Liguo Zhang
- & Q Richard Lu
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Letter |
Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities
This study identifies the concurrent activation of SHH and PI3K signaling by loss of PTEN as a frequent event in glioblastoma tumors that can be targeted with combination treatments using approved drugs to achieve antitumor responses in vivo. The results could potentially lead to the exploration of much needed new combination therapies for human brain tumors.
- Mariella Gruber Filbin
- , Sukriti K Dabral
- & Rosalind A Segal
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Article |
CSF-1R inhibition alters macrophage polarization and blocks glioma progression
The authors provide preclinical testing of a CSFR-1 inhibitor in proneural glioma models. The compound targets macrophages in the tumor microenvironment rather than tumor cells themselves and is shown to portend considerable antitumor effects. Its activity relies on re-education of tumor-associated macrophages without affecting their survival, reverting their tumor-promoting phenotype. Moreover, gene signatures capturing the tumorigenic features of macrophages can predict survival in human patients with glioma, underscoring the potential relevance of this strategy as a glioma therapy.
- Stephanie M Pyonteck
- , Leila Akkari
- & Johanna A Joyce
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Technical Report |
Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy
- Kyrre E Emblem
- , Kim Mouridsen
- & A Gregory Sorensen
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Article |
BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1
Branched-chain amino acid transaminase 1, the enzyme that initiates the catabolism of branched-chain amino acids, is involved in glioma pathogenesis, making it a potential therapeutic target.
- Martje Tönjes
- , Sebastian Barbus
- & Bernhard Radlwimmer
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A prognostic neural epigenetic signature in high-grade glioma
Reconstructing glioblastoma hierarchy
Inhibitors of rogue enzyme near trials for brain and blood tumors