Neuro-oncology最新文献

{"title":"Genome-wide CRISPR-Cas9 screens identify BCL family members as modulators of response to regorafenib in experimental glioma.","authors":"Lara Annina Haeusser, Hannes Becker, Laurence Kuhlburger, Marcello Zago, Bianca Walter, Foteini Tsiami, Sarah Erdmann, Jil Trampert, Surender Surender, Aaron Stahl, Markus Templin, Eileen Wegner, Tobias Schmidt, Christian Schmees, Nicolas Casadei, Lisa Sevenich, Manfred Claassen, Sven Nahnsen, Susanne Beck, Daniel Josef Merk, Ghazaleh Tabatabai","doi":"10.1093/neuonc/noae278","DOIUrl":"10.1093/neuonc/noae278","url":null,"abstract":"<p><strong>Background: </strong>Registered systemic treatment options for glioblastoma patients are limited. The phase II REGOMA trial suggested an improvement of median overall survival in progressive glioblastoma by the multi-tyrosine kinase inhibitor regorafenib. This has not been confirmed by GBM AGILE. So far, regorafenib has been administered as monotherapy or as an addition to standard of care in newly diagnosed glioblastoma. Rational combination therapies involving regorafenib might be a reasonable strategy. Here, we aimed at identifying functionally instructed combination therapies involving regorafenib.</p><p><strong>Methods: </strong>We applied a genome-wide CRISPR-Cas9-based functional genomics target discovery approach using activation and knockout screens followed by genetic, pharmacological, functional validations. Regorafenib-induced molecular alterations were assessed by RNA sequencing and DigiWest. We investigated selected functionally instructed combination therapies in three orthotopic glioma mouse models in vivo (syngeneic SMA560/VM/Dk model and two xenograft models) and performed immunohistochemistry of post-treatment brains.</p><p><strong>Results: </strong>We identified potential modifiers of regorafenib response, including BCL2, BCL2L1, ITGB3, FOXC1, SERAC1, ARAF, and PLCE1. The combination of regorafenib with Bcl-2/Bcl-xL inhibition was superior to both monotherapies alone in vitro, ex vivo, and in vivo. We identified regorafenib-induced regulations of the Bcl-2 downstream target chemokine receptor 1 (CCR1) as one potential underlying molecular mediator. Furthermore, regorafenib led to changes in the myeloid compartment of the glioma-associated microenvironment.</p><p><strong>Conclusions: </strong>This preclinical study uses a functional genomics-based target discovery approach with subsequent validations involving regorafenib. It serves as a biological rationale for clinical translation. Particularly, an investigation of the combination of regorafenib plus navitoclax within a clinical trial is warranted.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"916-931"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting processive transcription for Myc-driven circuitry in medulloblastoma.","authors":"Lays Martin Sobral, Faye M Walker, Krishna Madhavan, Elizabeth Janko, Sahiti Donthula, Etienne Danis, Pradeep Bompada, Ilango Balakrishnan, Dong Wang, Angela Pierce, Mary M Haag, Billie J Carstens, Natalie J Serkova, Nicholas K Foreman, Sujatha Venkataraman, Bethany Veo, Rajeev Vibhakar, Nathan A Dahl","doi":"10.1093/neuonc/noaf121","DOIUrl":"10.1093/neuonc/noaf121","url":null,"abstract":"<p><strong>Background: </strong>Medulloblastoma is the most common malignant brain tumor of childhood. The highest-risk tumors are driven by recurrent Myc amplifications (Myc-MB) and experience poorer outcomes despite intensive multimodal therapy. The Myc transcription factor defines core regulatory circuitry for these tumors and acts to broadly amplify downstream pro-survival transcriptional programs. Therapeutic targeting of Myc directly has proven elusive, but inhibiting transcriptional cofactors may present an indirect means of drugging the oncogenic transcriptional circuitry sustaining Myc-MB.</p><p><strong>Methods: </strong>Independent CRISPR-Cas9 screens were pooled to identify conserved dependencies in Myc-MB. We performed chromatin conformation capture (Hi-C) from primary patient Myc-MB samples to map enhancer-promoter interactions. We then treated in vitro and xenograft models with CDK9/7 inhibitors to evaluate effect on Myc-driven programs and tumor growth.</p><p><strong>Results: </strong>Eight CRISPR-Cas9 screens performed across three independent labs identify CDK9 as a conserved dependency in Myc-MB. Myc-MB cells are susceptible to CDK9 inhibition, which is synergistic with concurrent inhibition of CDK7. Inhibition of transcriptional CDKs disrupts enhancer-promoter activity in Myc-MB and downregulates Myc-driven transcriptional programs, exerting potent anti-tumor effect.</p><p><strong>Conclusions: </strong>Our findings identify CDK9 inhibition as a translationally promising strategy for the treatment of Myc-MB.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079222","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":"Inhibition of mitochondrial bioenergetics and hypoxia to radiosensitize diffuse intrinsic pontine glioma.","authors":"Han Shen, Faiqa Mudassar, Shiyong Ma, Xingyu Wang, Sandy Nguyen, Neha Bal, Quy-Susan Huynh, Dongwei Wang, Cecilia Chang, Prunella Ing, Winny Varikatt, Joey Lai, Brian Gloss, Jeff Holst, Geraldine M O'Neill, Harriet Gee, Kristina M Cook, Eric Hau","doi":"10.1093/neuonc/noae255","DOIUrl":"10.1093/neuonc/noae255","url":null,"abstract":"<p><strong>Background: </strong>Diffuse intrinsic pontine gliomas (DIPGs) and other H3K27M-mutated diffuse midline gliomas (DMGs) are brain tumors that primarily affect children. Radiotherapy is the standard of care but only provides only temporary symptomatic relief due to radioresistance. Although hypoxia is a major driver of radioresistance in other tumors, there is no definitive evidence that DIPGs are hypoxic. Diffuse intrinsic pontine gliomas often contain histone mutations, which alter tumor metabolism and are also associated with radioresistance. Our objective was to identify the metabolic profiles of DIPG cells, detect hypoxia signatures, and uncover metabolism-linked mechanisms of radioresistance to improve tumor radiosensitivity.</p><p><strong>Methods: </strong>Using DIPG models combined with clinical datasets, we examined mitochondrial metabolism and signatures of hypoxia. We explored DIPG reliance on mitochondrial metabolism using extracellular flux assays and targeted metabolomics. In vitro and in vivo models were used to explore the mechanisms of targeting mitochondrial bioenergetics and hypoxia for radiosensitization. Treatment-induced transcriptomics and metabolomics were also investigated.</p><p><strong>Results: </strong>Comprehensive analyses of DIPG cells show signatures of enhanced oxidative phosphorylation (OXPHOS). We also identified increased expression of specific OXPHOS-related genes and signatures of hypoxia gene expression in datasets obtained from DIPG patients. We found the presence of hypoxia in orthotopic mouse models bearing DIPG tumors. These findings enabled us to develop a proof-of-concept treatment strategy to enhance radiosensitivity of DIPGs in vitro and in animal models.</p><p><strong>Conclusions: </strong>Diffuse intrinsic pontine glioma cells rely on mitochondrial metabolism for growth, and targeting mitochondria disrupts bioenergetics, alleviates hypoxia, and enhances radiosensitivity. These findings warrant further exploration of OXPHOS inhibition as a radiosensitizing strategy for DIPG treatment.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1061-1075"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct epigenetic and transcriptional profiles of Epstein-Barr virus-positive and negative primary CNS lymphomas.","authors":"Ling Hai, Dennis Friedel, Felix Hinz, Dirk C Hoffmann, Sofia Doubrovinskaia, Hannah Rohdjess, Katharina Weidenauer, Evgeniya Denisova, Georg T Scheffler, Tobias Kessler, Alexandros Kourtesakis, Christel Herold-Mende, Octavian Henegariu, Joachim M Baehring, Jorg Dietrich, Benedikt Brors, Wolfgang Wick, Felix Sahm, Leon D Kaulen","doi":"10.1093/neuonc/noae251","DOIUrl":"10.1093/neuonc/noae251","url":null,"abstract":"<p><strong>Background: </strong>Epstein-Barr virus (EBV)+ and EBV- primary CNS lymphomas (PCNSL) carry distinct mutational landscapes, but their transcriptional and epigenetic profiles have not been integrated and compared. This precludes further insights into pathobiology and molecular differences, relevant for classification and targeted therapy.</p><p><strong>Methods: </strong>Twenty-three EBV- and 15 EBV+ PCNSL, histologically classified as diffuse large B-cell lymphomas, were subjected to RNA-sequencing and EPIC methylation arrays. Unsupervised clustering analyses were performed. Differentially expressed and differentially methylated genes were identified and integrated.</p><p><strong>Results: </strong>Two distinct transcriptional clusters were found, which separated EBV- and EBV+ PCNSL (P < .0001). The EBV+ transcriptional signature contained genes (GPR15, FCER2/CD23, SLAMF1/CD150) closely regulated by EBV oncogenes in B cells. Pathway enrichment analysis uncovered enhanced B-cell receptor (BCR) and WNT/beta-catenin signaling in EBV- lymphomas, whereas Interleukin-10, NOTCH, and viral life cycle pathways were upregulated in EBV+ PCNSL. Correspondingly, BCR-associated SYK kinase activity was enriched in EBV- tumors while JAK2 was overrepresented in EBV+ PCNSL. Epigenetic profiling revealed reduced global promoter methylation in EBV+ PCNSL. Two methylation clusters were recognized, which separated EBV- and EBV+ PCNSL (P < .0001). Epigenetic profiles were distinct from 2,788 other brain tumor and nonmalignant reference samples. Promoter region hypermethylation of CD79B, a BCR subunit critical for sustained proliferation in EBV- disease, highly correlated (R = -0.7) with its transcriptional downregulation in EBV+ PCNSL.</p><p><strong>Conclusions: </strong>EBV+ and EBV- PCNSL harbor distinct transcriptional and epigenetic profiles, corroborating them as distinctive biological subtypes. Uncovered differences provide novel insights into their pathobiology, may guide molecular diagnostics and targeted therapies.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"979-992"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic contrast-enhanced and diffusion-weighted MR imaging for predicting tumor growth of sporadic vestibular schwannomas: A prospective study.","authors":"Sammy M Schouten, Daniel Lewis, Stefan Cornelissen, Ka-Loh Li, Xiaoping Zhu, Marnix C Maas, Sjoert Pegge, Thijs T G Jansen, Jef J S Mulder, Jérôme J Waterval, Alida A Postma, Omar Pathmanaban, David J Coope, Jolanda M M Derks, Patrick P J H Langenhuizen, Andrew T King, Jeroen B Verheul, Henricus P M Kunst","doi":"10.1093/neuonc/noae252","DOIUrl":"10.1093/neuonc/noae252","url":null,"abstract":"<p><strong>Background: </strong>Advanced MR imaging, such as diffusion-weighted (DWI) and dynamic contrast-enhanced (DCE) imaging, may provide valuable noninvasive information on intrinsic tumor biology. This study aims to evaluate apparent diffusion coefficient (ADC) and DCE-MRI-derived microvascular parameter values (Ktrans, ve, and vp) as potential imaging predictors for future sporadic vestibular schwannoma (VS) growth.</p><p><strong>Methods: </strong>In this prospective cohort study, patients with newly diagnosed unilateral sporadic VS and an initial wait-and-scan strategy were enrolled between January 2021 and January 2023. Patients underwent a single timepoint comprehensive MRI protocol, including DWI and DCE-MRI sequences. The estimated values of ADC, Ktrans, ve, and vp were calculated using established pipelines on a voxelwise basis within the delineated tumor region of interest. Associations of the estimated parameter values with volumetric growth were evaluated in uni- and multivariable logistic regression and survival analyses.</p><p><strong>Results: </strong>Of the 110 analyzed patients, 70 (64%) exhibited growth during follow-up. A significant correlation was primarily observed between the DCE-MRI-derived parameters and VS growth. The combination of mean Ktrans (P < .001) and ve (P < .001) tumor values provided an internally validated model with an AUC of 0.85 for growth, yielding a sensitivity of 89% and specificity of 73% at the optimized cutoff value. Only the mean ADC values were found to be significantly higher in shrinking tumors (P = .04).</p><p><strong>Conclusions: </strong>The strongly significant correlation observed between VS growth and Ktrans and ve tumor values indicate the great potential of the noninvasive DCE-MRI for individualized VS management in clinical practice. External validation is needed to further substantiate these findings.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1116-1127"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic features underlying meningioma sex-specificity.","authors":"David R Raleigh","doi":"10.1093/neuonc/noaf002","DOIUrl":"10.1093/neuonc/noaf002","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1029-1030"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O-GlcNAcylation stabilized WTAP promotes GBM malignant progression in an N6-methyladenosine-dependent manner.","authors":"Jiawei Qiu, Rongrong Zhao, Caizhi Ma, Qingtong Wang, Boyan Li, Yanhua Qi, Ziwen Pan, Shulin Zhao, Shaobo Wang, Zijie Gao, Xiaofan Guo, Wei Qiu, Weijie Tang, Xing Guo, Lin Deng, Hao Xue, Gang Li","doi":"10.1093/neuonc/noae268","DOIUrl":"10.1093/neuonc/noae268","url":null,"abstract":"<p><strong>Background: </strong>Interactions between mesenchymal glioblastoma stem cells (MES GSCs) and myeloid-derived macrophages (MDMs) shape the tumor-immunosuppressive microenvironment (TIME), promoting the progression of glioblastoma (GBM). N6-methyladenosine (m6A) plays important roles in the tumor progression. However, the mechanism of m6A in shaping the TIME of GBM remains elusive.</p><p><strong>Methods: </strong>Single-cell RNA sequencing and bulk RNA-seq datasets were employed to identify the critical role of WTAP in interactions between MES GBM and MDMs. The biological function of WTAP was confirmed both in vitro and in vivo. Mechanistically, mass spectrum, RNA immunoprecipitation (RIP), and co-immunoprecipitation assays were conducted.</p><p><strong>Results: </strong>Here, we identified that m6A methyltransferase Wilms' tumor 1-associated protein (WTAP), whose protein stability could be synergistically enhanced via OGT-mediated O-GlcNAcylation and USP7-mediated de-ubiquitination, promoted LOXL2 m6A modification to enhance its mRNA stabilization in an IGF2BP2-dependent manner, upregulating secretion of LOXL2 protein (sLOXL2). sLOXL2 then interacted with integrin α5β1 on GSCs to activate FAK-ERK signaling, inducing mesenchymal transition of GSCs in an autocrine manner. Meanwhile, sLOXL2 also activated the integrin α5β1-FAK-ERK axis in MDMs, which promoted M2-like MDM phenotypes in a paracrine pathway, thereby contributing to T-cell exhaustion to induce GBM immune escape. In translational medicine, combinations of the OGT inhibitor by targeting WTAP expression and the LOXL2 antagonist by disrupting MES GSC and MDM interactions showed favorable outcomes to the anti-PD1 immunotherapy.</p><p><strong>Conclusions: </strong>WTAP plays critical roles in mesenchymal transition of GSCs and formation of TIME, highlighting the therapeutic potential of targeting WTAP and its downstream effectors to enhance the efficacy of immunotherapy.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"900-915"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracing tumor-neuronal connectivity in glioblastoma.","authors":"Sean E Lawler","doi":"10.1093/neuonc/noaf005","DOIUrl":"10.1093/neuonc/noaf005","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"867-868"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"European Association of Neuro-Oncology guideline on molecular testing of meningiomas for targeted therapy selection.","authors":"Felix Sahm, Luca Bertero, Sebastian Brandner, David Capper, Roland Goldbrunner, Michael D Jenkinson, Michel Kalamarides, Katrin Lamszus, Nathalie L Albert, Maximilian J Mair, Anna S Berghoff, Christian Mawrin, Hans-Georg Wirsching, Sybren L N Maas, David R Raleigh, Guido Reifenberger, Leonille Schweizer, Abigail K Suwala, Ghazaleh Tabatabai, Emeline Tabouret, Susan Short, Patrick Y Wen, Michael Weller, Emilie Le Rhun, Pieter Wesseling, Martin van den Bent, Matthias Preusser","doi":"10.1093/neuonc/noae253","DOIUrl":"10.1093/neuonc/noae253","url":null,"abstract":"<p><p>Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4,ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGF(R), PDGFR, as well as homologous recombination deficiency, genomic copy number variations, DNA methylation classes, and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence-level criteria, no molecular target reached ESCAT I (\"ready for clinical use\") classification, and only mTOR pathway activation and NF2 alterations reached ESCAT II (\"investigational\") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"869-883"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using a pre-radiation window to identify potentially active cytotoxic agents in adults with newly diagnosed glioblastoma.","authors":"Danielle A Bazer, Antonio C Wolff, Stuart A Grossman","doi":"10.1093/neuonc/noae240","DOIUrl":"10.1093/neuonc/noae240","url":null,"abstract":"<p><p>Therapies shown to improve outcomes in patients with recurrent cancers are commonly used in the neoadjuvant setting to optimize surgery, reduce radiation fields, and treat micrometastatic disease. While the use of pre-radiation chemotherapy (PRC) has flourished in systemic cancers, it has not seen the same level of use in glioblastomas. This review documents these trajectories and highlights the potential of PRC to rapidly and safely screen cytotoxic drugs for efficacy in patients with newly diagnosed glioblastoma. Prospective trials of adults with newly diagnosed systemic and brain cancers treated with PRC published between 1980 and 2023 were identified in PubMed. The National Comprehensive Cancer Network guidelines were used to document the standard use of PRC in patients with systemic and brain cancers. Over 5000 prospective PRC trials in solid tumors were identified. These accrued  >1 million patients and resulted in neoadjuvant therapies being the standard of care in ~28 systemic cancers. Only 50 similar trials (2206 patients) were identified in high-grade gliomas. In 13 trials containing PRC temozolomide (n = 846), radiographic responses ranged from 6 to 53% with a median survival of ~13 months. Glioblastoma PRC trials were not associated with unexpected toxicities or major negative impacts on survival. Pre-radiation chemotherapy in patients with glioblastoma appears safe and feasible. The pre-radiation window is ideally suited to rapidly screen cytotoxic agents for efficacy. It permits radiographic response as a primary outcome, small sample sizes, and initiation of standard therapies a few months after diagnosis. Pre-radiation chemotherapy may be most appropriate for patients with glioblastoma who are unlikely to benefit from temozolomide.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"884-896"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}