Neuro-oncology最新文献

{"title":"Intracranial administration of anti-PD-1 and anti-CTLA-4 immune checkpoint-blocking monoclonal antibodies in patients with recurrent high-grade glioma.","authors":"Johnny Duerinck, Louise Lescrauwaet, Iris Dirven, Jacomi Del'haye, Latoya Stevens, Xenia Geeraerts, Freya Vaeyens, Wietse Geens, Stefanie Brock, Anne-Marie Vanbinst, Hendrik Everaert, Ben Caljon, Michaël Bruneau, Laetitia Lebrun, Isabelle Salmon, Marc Kockx, Sandra Tuyaerts, Bart Neyns","doi":"10.1093/neuonc/noae177","DOIUrl":"https://doi.org/10.1093/neuonc/noae177","url":null,"abstract":"<p><strong>Background: </strong>Recurrent high-grade glioma (rHGG) lacks effective life-prolonging treatments and the efficacy of systemic PD-1 and CTLA-4 immune checkpoint inhibitors is limited. The multi-cohort Glitipni phase I trial investigates the safety and feasibility of intraoperative intracerebral (iCer) and postoperative intracavitary (iCav) nivolumab (NIVO) ± ipilimumab (IPI) treatment following maximal safe resection (MSR) in rHGG.</p><p><strong>Materials and methods: </strong>Patients received 10 mg IV NIVO within 24 h before surgery, followed by MSR, iCer 5 mg IPI and 10 mg NIVO, and Ommaya catheter placement in the resection cavity. Biweekly postoperative iCav administrations of 1-5-10 mg NIVO (cohort 4) or 10 mg NIVO plus 1-5-10 mg IPI (cohort 7) were combined with 10 mg IV NIVO for 11 cycles.</p><p><strong>Results: </strong>42 rHGG patients underwent MSR with iCer NIVO + IPI. 16 pts were treated in cohort 4 (postoperative iCav NIVO at escalating doses) while 28 patients were treated in cohort 7 (intra and postoperative iCav NIVO and escalating doses of IPI). The most common TRAE was fatigue; no grade 5 AE occurred. Dose-limiting toxicity was grade 3 neutrophilic pleocytosis (4 pts) receiving iCav NIVO plus 5 or 10 mg IPI. PFS and OS did not significantly differ between cohorts (median OS: 42 [95% CI 26-57] vs. 35 [29-40] weeks; 1-year OS rate: 37% vs. 29%). Baseline B7-H3 expression significantly correlated with worse survival. OS compared favorably to a historical pooled cohort (n = 469) of Belgian rHGG pts treated with anti-VEGF therapies (log-rank P = .015).</p><p><strong>Conclusion: </strong>Intraoperative iCer IPI + NIVO with postoperative iCav NIVO ± IPI up to biweekly doses of 1 mg IPI + 10 mg NIVO is feasible and safe, showing encouraging OS in rHGG patients. ClinicalTrials.gov registration: NCT03233152.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Immune Landscape in Brain Metastasis.","authors":"Luca D Schreurs, Alexander F Vom Stein, Stephanie T Jünger, Marco Timmer, Ka-Won Noh, Reinhard Buettner, Hamid Kashkar, Volker Neuschmelting, Roland Goldbrunner, Phuong-Hien Nguyen","doi":"10.1093/neuonc/noae219","DOIUrl":"https://doi.org/10.1093/neuonc/noae219","url":null,"abstract":"<p><p>The prognosis for patients with brain metastasis remains dismal despite intensive therapy including surgical resection, radiotherapy, chemo-, targeted and immunotherapy. Thus, there is a high medical need for new therapeutic options. Recent advances employing high-throughput and spatially resolved single-cell analyses have provided unprecedented insights into the composition and phenotypes of the diverse immune cells in the metastatic brain, revealing a unique immune landscape starkly different from that of primary brain tumours or other metastatic sites. This review summarises the current evidence on the composition and phenotypes of the most prominent immune cells in the brain metastatic niche, along with their dynamic interactions with metastatic tumour cells and each other. As the most abundant immune cell types in this niche, we explore in detail the phenotypic heterogeneity and functional plasticity of tumour-associated macrophages, including both resident microglia and monocyte-derived macrophages, as well as the T-cell compartment. We also review pre-clinical and clinical trials evaluating the therapeutic potential of targeting the immune microenvironment in brain metastasis. Given the substantial evidence highlighting a significant role of the immune microenvironmental niche in brain metastasis pathogenesis, a comprehensive understanding of the key molecular and cellular factors within this niche holds great promise for developing novel therapeutic approaches as well as innovative combinatory treatment strategies for brain metastasis.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma.","authors":"Matthew Gallitto, Xu Zhang, Genesis De Los Santos, Hong-Jian Wei, Ester Calvo Fernández, Shoufu Duan, Geoffrey Sedor, Nina Yoh, Danae Kokosi, J Carlos Angel, Yi-Fang Wang, Erin White, Connor J Kinslow, Xander Berg, Lorenzo Tomassoni, Fereshteh Zandkarimi, Iok In Christine Chio, Peter D Canoll, Jeffrey N Bruce, Neil A Feldstein, Robyn D Gartrell, Simon Cheng, James H Garvin, Stergios Zacharoulis, Robert J Wechsler-Reya, Jovana Pavisic, Andrea Califano, Zhiguo Zhang, Cheng-Chia Wu","doi":"10.1093/neuonc/noae215","DOIUrl":"https://doi.org/10.1093/neuonc/noae215","url":null,"abstract":"<p><strong>Background: </strong>Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. All previous studies examining the role of systemic agents have failed to demonstrate a survival benefit; the only standard of care is radiation therapy (RT). Successful implementation of radiosensitization strategies in DMG remains an essential and promising avenue of investigation. We explore the use of Napabucasin, an NAD(P)H quinone dehydrogenase 1 (NQO1)-bioactivatable reactive oxygen species (ROS)-inducer, as a potential therapeutic radiosensitizer in DMG.</p><p><strong>Methods: </strong>In this study, we conduct in vitro and in vivo assays using patient-derived DMG cultures to elucidate the mechanism of action of Napabucasin and its radiosensitizing properties. As penetration of systemic therapy through the blood-brain barrier (BBB) is a significant limitation to the success of DMG therapies, we explore focused ultrasound (FUS) and convection-enhanced delivery (CED) to overcome the BBB and maximize therapeutic efficacy.</p><p><strong>Results: </strong>Napabucasin is a potent ROS-inducer and radiosensitizer in DMG, and treatment-mediated ROS production and cytotoxicity are dependent on NQO1. In subcutaneous xenograft models, combination therapy with RT improves local control. After optimizing targeted drug delivery using CED in an orthotopic mouse model, we establish the novel feasibility and survival benefit of CED of Napabucasin concurrent with RT.</p><p><strong>Conclusions: </strong>As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pediatric Cranial Stereotactic Radiosurgery: Meta-Analysis and International Stereotactic Radiosurgery Society Practice Guidelines.","authors":"Erin S Murphy, Arjun Sahgal, Jean Regis, Marc Levivier, Laura Fariselli, Alessandra Gorgulho, Lijun Ma, Bruce Pollock, Shoji Yomo, Jason Sheehan, Ian Paddick, John H Suh, Anshul Saxena, Md Ashfaq Ahmed, Rupesh Kotecha","doi":"10.1093/neuonc/noae204","DOIUrl":"https://doi.org/10.1093/neuonc/noae204","url":null,"abstract":"<p><strong>Background: </strong>There are limited data on the use of stereotactic radiosurgery (SRS) for pediatric patients. The aim of this systematic review was to summarize indications and outcomes specific to pediatric cranial SRS to inform consensus guidelines on behalf of the International Stereotactic Radiosurgery Society (ISRS).</p><p><strong>Methods: </strong>A systematic review, using the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), analyzed English-language articles on SRS, published between 1989 and 2021, that included outcomes for at least 5 pediatric patients. MEDLINE database terms included tumor types and locations, and radiosurgical and age-specific terms. We excluded nonclinical reports, expert opinions, commentaries, and review articles. Meta-regressions for associations with local control were performed for medulloblastoma, craniopharyngioma, ependymoma, glioma, and arteriovenous malformation (AVM).</p><p><strong>Results: </strong>Of the 113 articles identified for review, 68 met the inclusion criteria. These articles described approximately 400 pediatric patients with benign and malignant brain tumors and 5119 with AVMs who underwent cranial SRS. The rates of local control for benign tumors, malignant tumors, and AVMs were 89% (95% CI, 82%-95%), 71% (95% CI, 59%-82%), and 65% (95% CI, 60%-69%), respectively. No significant associations were identified for local control with patient-, tumor-, or treatment-related variables.</p><p><strong>Conclusions: </strong>This review is the first to summarize outcomes specific to SRS for pediatric brain tumors and AVMs. Although data reporting is limited for pediatric patients, SRS appears to provide acceptable rates of local control. We present ISRS consensus guidelines to inform the judicious use of cranial SRS for pediatric patients.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic combination of perphenazine and temozolomide suppresses patient-derived glioblastoma tumorspheres.","authors":"Jun Pyo Hong, Ran Joo Choi, Jin-Kyoung Shim, Kibyeong Kim, Ryong Nam Kim, Hye Joung Cho, Seo Jin Kim, Sohyun Kim, Nam Hwa Kim, Hun Ho Park, Ju Hyung Moon, Eui Hyun Kim, Wan-Yee Teo, Seungsoo Chung, Jong Hee Chang, Seok-Gu Kang","doi":"10.1093/neuonc/noae211","DOIUrl":"https://doi.org/10.1093/neuonc/noae211","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs).</p><p><strong>Methods: </strong>The biological effects of the combination of PER and TMZ in GBM TSs were assessed by measuring cell viability, ATP, stemness, invasiveness, and apoptosis. Changes in protein and mRNA expression were analyzed using western blotting and RNA sequencing. Co-administration of PER and TMZ was evaluated in vivo using a mouse orthotopic xenograft model.</p><p><strong>Results: </strong>The Severance dataset showed that DRD2 and DRD3 expression was higher in tumor tissues than in the tumor-free cortex of patients with GBM. DRD2/3 knockout by CRISPR/Cas9 in patient-derived human GBM TSs inhibited cell growth and ATP production. The combined treatment with PER and TMZ resulted in superior effects on cell viability and ATP assays compared to those in single treatment groups. Flow cytometry, western blotting, and RNA sequencing confirmed elevated apoptosis in GBM TSs following combination treatment. Additionally, the combination of PER and TMZ downregulated the expression of protein and mRNA associated with stemness and invasiveness. In vivo evaluation showed that combining PER and TMZ extended the survival period of the mouse orthotopic xenograft model.</p><p><strong>Conclusions: </strong>The synergistic combination of PER and TMZ has potential as a novel combination treatment strategy for GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Updated EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection - Update 1.","authors":"Martin J van den Bent, Enrico Franceschi, Mehdi Touat, Pim J French, Ahmed Idbaih, Giuseppe Lombardi, Roberta Rudaà, Leonille Schweizer, David Capper, Marc Sanson, Pieter Wesseling, Michael Weller, Marica Eoli, Elena Anghileri, Franck Bielle, Phillipp Euskirchen, Marjolein Geurts, Patrick Y Wen, Matthias Preusser","doi":"10.1093/neuonc/noae213","DOIUrl":"https://doi.org/10.1093/neuonc/noae213","url":null,"abstract":"<p><p>The standard of care for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a major part of the standard treatment, however, the predictive significance of most of the targets for treatment in systemic cancer are less well established in central nervous system (CNS) tumors . In 2023 the EANO Guideline Committee presented evidence based recommendations for rational testing of molecular targets for targeted treatments. From all targets reviewed, only testing for BRAF V600E mutations was of proven clinical benefit; despite regulatory approvals for tumor agnostic treatment of NTRK gene fusions and high Tumor Mutational Burden (TMB) for patients with adult brain tumors, the evidence of clinical benefit for patients was still limited . This guideline has a modular structure, allowing regular updating of individual sections and adding new ones. The present version (Update 1) presents a review of the rationale of testing for PTEN, H3F3A, MTAP, RET and IDH, and presents an update of the text on TMB high and mismatch repair deficiency. It also presents an overview of therapeutic yield of routine next generation sequencing for mutations and fusion detection. The supplement accompanying this version contains the in depth review of all targets, whereas in the main manuscript the final recommendations of the revised and new targets are presented. Updates will be made on a regular basis.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing.","authors":"Niek van Bree, Ann-Sophie Oppelt, Susanne Lindström, Leilei Zhou, Lola Boutin, Beth Coyle, Fredrik J Swartling, John Inge Johnsen, Lars Bräutigam, Margareta Wilhelm","doi":"10.1093/neuonc/noae210","DOIUrl":"https://doi.org/10.1093/neuonc/noae210","url":null,"abstract":"<p><strong>Background: </strong>Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinical in vivo model systems for MB have increased our understanding of molecular mechanisms regulating MB development. However, they may not be suitable for large-scale studies. The aim of this study was to investigate if a zebrafish-based xenograft model can recapitulate MB growth and enable rapid drug testing.</p><p><strong>Methods: </strong>Nine different MB cell lines or patient-derived cells were transplanted into blastula-stage zebrafish embryos. Tumor development and migration were then monitored using live imaging. RNA sequencing was performed to investigate transcriptome changes after conditioning cells in neural stem cell-like medium. Furthermore, drug treatments were tested in a 96-well format.</p><p><strong>Results: </strong>We demonstrate here that transplantation of MB cells into the blastula stage of zebrafish embryos leads to orthotopic tumor growth that can be observed within 24 hours after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome towards a more migratory and neuronal phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB model has the potential to be used for rapid drug testing.</p><p><strong>Conclusion: </strong>Blastula-stage zebrafish MB xenografts present an alternative to current MB mouse xenograft models, enabling quick evaluation of tumor cell growth, neurotropism, and drug efficacy.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study.","authors":"Edward C Schwalbe, Janet C Lindsey, Marina Danilenko, Rebecca M Hill, Stephen Crosier, Sarra L Ryan, Daniel Williamson, Jemma Castle, Debbie Hicks, Marcel Kool, Till Milde, Andrey Korshunov, Stefan M Pfister, Simon Bailey, Steven C Clifford","doi":"10.1093/neuonc/noae178","DOIUrl":"https://doi.org/10.1093/neuonc/noae178","url":null,"abstract":"<p><strong>Background: </strong>MYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients' MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management.</p><p><strong>Methods: </strong>We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases.</p><p><strong>Results: </strong>Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a \"canonical\" very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS.</p><p><strong>Conclusions: </strong>MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR \"canonical\" MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYC-dependent upregulation of the de novo serine and glycine synthesis pathway is a targetable metabolic vulnerability in group 3 medulloblastoma.","authors":"Magretta Adiamah, Bethany Poole, Janet C Lindsey, Sarah Kohe, Alaide Morcavallo, Florence Burté, Rebecca M Hill, Helen Blair, Dean Thompson, Mankaran Singh, Shanel Swartz, Stephen Crosier, Tong Zhang, Oliver D K Maddocks, Andrew Peet, Louis Chesler, Ian Hickson, Ross J Maxwell, Steven C Clifford","doi":"10.1093/neuonc/noae179","DOIUrl":"https://doi.org/10.1093/neuonc/noae179","url":null,"abstract":"<p><strong>Background: </strong>Group 3 medulloblastoma (MBGRP3) represents around 25% of medulloblastomas and is strongly associated with c-MYC (MYC) amplification, which confers significantly worse patient survival. Although elevated MYC expression is a significant molecular feature in MBGRP3, direct targeting of MYC remains elusive, and alternative strategies are needed. The metabolic landscape of MYC-driven MBGRP3 is largely unexplored and may offer novel opportunities for therapies.</p><p><strong>Methods: </strong>To study MYC-induced metabolic alterations in MBGRP3, we depleted MYC in isogenic cell-based model systems, followed by 1H high-resolution magic-angle spectroscopy (HRMAS) and stable isotope-resolved metabolomics, to assess changes in intracellular metabolites and pathway dynamics.</p><p><strong>Results: </strong>Steady-state metabolic profiling revealed consistent MYC-dependent alterations in metabolites involved in one-carbon metabolism such as glycine. 13C-glucose tracing further revealed a reduction in glucose-derived serine and glycine (de novo synthesis) following MYC knockdown, which coincided with lower expression and activity of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in this pathway. Furthermore, MYC-overexpressing MBGRP3 cells were more vulnerable to pharmacological inhibition of PHGDH compared to those with low expression. Using in vivo tumor-bearing genetically engineered and xenograft mouse models, pharmacological inhibition of PHGDH increased survival, implicating the de novo serine/glycine synthesis pathway as a pro-survival mechanism sustaining tumor progression. Critically, in primary human medulloblastomas, increased PHGDH expression correlated strongly with both MYC amplification and poorer clinical outcomes.</p><p><strong>Conclusions: </strong>Our findings support a MYC-induced dependency on the serine/glycine pathway in MBGRP3 that represents a novel therapeutic treatment strategy for this poor prognosis disease group.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma.","authors":"Lynnette Wei Hsien Koh, Qing You Pang, Wisna Novera, See Wee Lim, Yuk Kien Chong, Jinyue Liu, Samantha Ya Lyn Ang, Ron Weng Yee Loh, Huilin Shao, Jianhong Ching, Yulan Wang, Stephen Yip, Patrick Tan, Shang Li, David Chyi Yeu Low, Anne Phelan, Gabriel Rosser, Nguan Soon Tan, Carol Tang, Beng Ti Ang","doi":"10.1093/neuonc/noae206","DOIUrl":"https://doi.org/10.1093/neuonc/noae206","url":null,"abstract":"<p><strong>Background: </strong>EZH2, well-known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied non-canonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical SET domain show limited efficacy and lack durable response, suggesting that underlying differences in the non-canonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically-distinct, reactive oxygen species (ROS)-stratified tumors.</p><p><strong>Methods: </strong>We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts.</p><p><strong>Results: </strong>In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of non-canonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, PRC2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its non-methyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice.</p><p><strong>Conclusion: </strong>Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its non-canonical activities and underscoring the significance of patient stratification methodologies.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}