ABSTRACT
DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.
Subject(s)
Brain Neoplasms , DNA Damage , Humans , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Brain Neoplasms/pathology , Translational Research, Biomedical , Animals , DNA Repair , Glioma/genetics , Glioma/therapy , Glioma/pathology , Consensus , MutationABSTRACT
Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median overall survival of less than 2 years and a nearly 100% mortality rate under standard therapy that consists of surgery followed by combined radiochemotherapy. Therefore, new therapeutic strategies are urgently needed. The success of chimeric antigen receptor (CAR) T cells in hematological cancers has prompted preclinical and clinical investigations into CAR-T-cell treatment for GBM. However, recent trials have not demonstrated any major success. Here, we delineate existing challenges impeding the effectiveness of CAR-T-cell therapy for GBM, encompassing the cold (immunosuppressive) microenvironment, tumor heterogeneity, T-cell exhaustion, local and systemic immunosuppression, and the immune privilege inherent to the central nervous system (CNS) parenchyma. Additionally, we deliberate on the progress made in developing next-generation CAR-T cells and novel innovative approaches, such as low-intensity pulsed focused ultrasound, aimed at surmounting current roadblocks in GBM CAR-T-cell therapy.
Subject(s)
Glioblastoma , Immunotherapy, Adoptive , Receptors, Chimeric Antigen , Humans , Glioblastoma/therapy , Glioblastoma/immunology , Immunotherapy, Adoptive/methods , Receptors, Chimeric Antigen/immunology , Tumor Microenvironment/immunology , Brain Neoplasms/therapy , Brain Neoplasms/immunology , T-Lymphocytes/immunology , AnimalsABSTRACT
The prognosis of patients with glioblastoma (GBM) remains poor despite current treatments. Targeted therapy in GBM has been the subject of intense investigation but has not been successful in clinical trials. The reasons for the failure of targeted therapy in GBM are multifold and include a lack of patient selection in trials, the failure to identify driver mutations, and poor blood-brain barrier penetration of investigational drugs. Here, we describe a case of a durable complete response in a newly diagnosed patient with GBM with leptomeningeal dissemination and PTPRZ1-MET fusion who was treated with tepotinib, a brain-penetrant MET inhibitor. This case of successful targeted therapy in a patient with GBM demonstrates that early molecular testing, identification of driver molecular alterations, and treatment with brain-penetrant small molecule inhibitors have the potential to change the outcome in select patients with GBM.
ABSTRACT
PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.
Subject(s)
Antineoplastic Agents , Brain Neoplasms , Glioblastoma , Humans , Blood-Brain Barrier/pathology , Glioblastoma/drug therapy , Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Drug Delivery Systems , Tumor MicroenvironmentABSTRACT
PURPOSE: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. METHODS: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. RESULTS: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. CONCLUSION: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.
Subject(s)
Brain Neoplasms , Glioma , Histones , Mutation , Humans , Adult , Female , Male , Adolescent , Middle Aged , Young Adult , Glioma/genetics , Glioma/drug therapy , Glioma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Child , Histones/genetics , Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/drug therapy , Child, Preschool , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Pyridones/therapeutic useABSTRACT
Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope (n = 3), fatigue (n = 1), wound infection (n = 2), and pain at time of device connection (n = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery.
Subject(s)
Blood-Brain Barrier , Glioblastoma , Humans , Carboplatin/adverse effects , Blood-Brain Barrier/pathology , Glioblastoma/diagnostic imaging , Glioblastoma/drug therapy , Ultrasonography , Biological Transport , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Response Assessment in Neuro-Oncology (RANO) response criteria have been established and were updated in 2023 for MRI-based response evaluation of diffuse gliomas in clinical trials. In addition, PET-based imaging with amino acid tracers is increasingly considered for disease monitoring in both clinical practice and clinical trials. So far, a standardised framework defining timepoints for baseline and follow-up investigations and response evaluation criteria for PET imaging of diffuse gliomas has not been established. Therefore, in this Policy Review, we propose a set of criteria for response assessment based on amino acid PET imaging in clinical trials enrolling participants with diffuse gliomas as defined in the 2021 WHO classification of tumours of the central nervous system. These proposed PET RANO criteria provide a conceptual framework that facilitates the structured implementation of PET imaging into clinical research and, ultimately, clinical routine. To this end, the PET RANO 1.0 criteria are intended to encourage specific investigations of amino acid PET imaging of gliomas.
Subject(s)
Glioma , Neurology , Humans , Glioma/diagnostic imaging , Glioma/therapy , Amino Acids , Internal Medicine , Positron-Emission Tomography , Transcription FactorsABSTRACT
Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.
Subject(s)
Brain Neoplasms , Glioblastoma , Adult , Humans , Child , Middle Aged , Aged , Glioblastoma/genetics , Glioblastoma/pathology , Immune Checkpoint Inhibitors , Homozygote , Prospective Studies , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Sequence Deletion , Mutation/genetics , Isocitrate Dehydrogenase/geneticsABSTRACT
Background: Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%-50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment. We tested the therapeutic potential of MEK1/2 inhibitors in glioblastoma using 3D cultures of glioma stem-like cells (GSCs) and mouse models of glioblastoma. Methods: Several MEK inhibitors were screened in an unbiased high-throughput platform using GSCs. Cell death was evaluated using flow cytometry and Western blotting (WB) analysis. RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and WB analysis were used to identify and validate neuronal differentiation. Results: Unbiased screening of multiple MEK inhibitors in GSCs showed antiproliferative and apoptotic cell death in sensitive cell lines. An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4). We validated the neuronal differentiation phenotypes in vitro and in vivo using selected differentiation markers (ß-III-tubulin, ASCL1, DLL3, and NeuroD4). Oral treatment with trametinib in an orthotopic GSC xenograft model significantly improved animal survival, with 25%-30% of mice being long-term survivors. Conclusions: Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling.
ABSTRACT
PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. METHODS: Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0). RESULTS: We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment. CONCLUSION: The revised RANO 2.0 criteria refine response assessment in gliomas.
Subject(s)
Brain Neoplasms , Glioma , Humans , Adult , Brain Neoplasms/drug therapy , Reproducibility of Results , Neoplasm Recurrence, Local , Glioma/pathology , Magnetic Resonance Imaging/methodsABSTRACT
Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.
Subject(s)
Brain Neoplasms , Glioma , Humans , Glioma/genetics , Glioma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Histones/genetics , Treatment Outcome , Epigenesis, Genetic , MutationABSTRACT
Cytokines play an important role in regulating the immune response. Although there is great interest in exploiting cytokines for cancer immunotherapy, their clinical potential is limited by their pleiotropic properties and instability. A variety of cancer cell-intrinsic and extrinsic characteristics pose a barrier to effective treatments including cytokines. Recent studies using gene and cell therapy offer new opportunities for targeting cytokines or their receptors, demonstrating that they are actionable targets. Current efforts such as virotherapy, systemic cytokine therapy, and cellular and gene therapy have provided novel strategies that incorporate cytokines as potential therapeutic strategies for glioblastoma. Ongoing research on characterizing the tumor microenvironment will be informative for prioritization and combinatorial strategies of cytokines for future clinical trials. Unique therapeutic opportunities exist at the convergence of cytokines that play a dual role in tumorigenesis and immune modulation. Here, we discuss the underlying strategies in pre- and clinical trials aiming to enhance treatment outcomes in glioblastoma patients.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/drug therapy , Brain Neoplasms/drug therapy , Drug DevelopmentABSTRACT
Inner ear disorders are among the most common congenital abnormalities; however, current tissue culture models lack the cell type diversity to study these disorders and normal otic development. Here, we demonstrate the robustness of human pluripotent stem cell-derived inner ear organoids (IEOs) and evaluate cell type heterogeneity by single-cell transcriptomics. To validate our findings, we construct a single-cell atlas of human fetal and adult inner ear tissue. Our study identifies various cell types in the IEOs including periotic mesenchyme, type I and type II vestibular hair cells, and developing vestibular and cochlear epithelium. Many genes linked to congenital inner ear dysfunction are confirmed to be expressed in these cell types. Additional cell-cell communication analysis within IEOs and fetal tissue highlights the role of endothelial cells on the developing sensory epithelium. These findings provide insights into this organoid model and its potential applications in studying inner ear development and disorders.
Subject(s)
Endothelial Cells , Vestibule, Labyrinth , Humans , Cochlea/metabolism , Epithelium/metabolism , Organoids/metabolismSubject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/drug therapy , Brain Neoplasms/therapy , Research Design , Data AnalysisABSTRACT
Background: Medulloblastoma in adults is rare and treatment decisions are largely driven from pediatric literature. We sought to characterize recurrent medulloblastoma in adults. Methods: From a single-institution dataset of 200 adult patients diagnosed with medulloblastoma during 1978-2017, those with recurrence were analyzed for clinical features, treatment, and outcome. Results: Of the 200 patients, 82 (41%) with median age of 29 years (18-59) had recurrence after a median follow-up time of 8.4 years (95% CI = 7.1, 10.3). Of these, 30 (37%) were standard-risk, 31 (38%) were high-risk, and 21 (26%) had unknown-risk diseases at the time of initial diagnosis. Forty-eight (58%) presented with recurrence outside the posterior fossa, of whom 35 (43%) had distant recurrence only. Median Progression-free survival (PFS) and OS from initial surgery were 33.5 and 62.4 months, respectively. Neither PFS nor OS from initial diagnosis differed between the standard-risk and high-risk groups in those who experience recurrence (P = .505 and .463, respectively). Median OS from first recurrence was 20.3 months, also with no difference between the standard-risk and high-risk groups (P = .518). Recurrences were treated with combinations of re-resection (20 patients; 25%), systemic chemotherapy (61 patients; 76%), radiation (29 patients; 36%), stem cell transplant (6 patients; 8%), and intrathecal chemotherapy (4 patients; 5%). Patients who received radiation at recurrence had better OS (32.9 months) than those who did not (19.2 months) (P = .034). Conclusions: Recurrent medulloblastoma in adults has a poor prognosis irrespective of initial risk stratification. Recurrence commonly arises outside the posterior fossa years after initial diagnosis.
ABSTRACT
Successful drug development for people with cancers of the CNS has been challenging. There are multiple barriers to successful drug development including biological factors, rarity of the disease, and ineffective use of clinical trials. Based upon a series of presentations at the First Central Nervous System Clinical Trials Conference hosted by the American Society of Clinical Oncology and the Society for Neuro-Oncology, we provide an overview on drug development and novel trial designs in neuro-oncology. This Review discusses the challenges of therapeutic development in neuro-oncology and proposes strategies to improve the drug discovery process by enriching the pipeline of promising therapies, optimising trial design, incorporating biomarkers, using external data, and maximising efficacy and reproducibility of clinical trials.