Neuro-oncology最新文献

{"title":"The time has come for an integrated and multiscale grading system for oligodendrogliomas IDH-mutant and 1p/19q co-deleted mixing imaging and histomolecular parameters.","authors":"Johan Pallud","doi":"10.1093/neuonc/noaf022","DOIUrl":"10.1093/neuonc/noaf022","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1128-1129"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013296","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":"Validation and next-generation update of a DNA methylation-based recurrence predictor for meningioma: A multicenter prospective study.","authors":"Alexander P Landry, Justin Z Wang, Vikas Patil, Chloe Gui, Yasin Mamatjan, Zeel Patel, Rebecca Yakubov, Ramneet Kaloti, Parnian Habibi, Mark Wilson, Andrew Ajisebutu, Yosef Ellenbogen, Qingxia Wei, Olivia Singh, Julio Sosa, Sheila Mansouri, Christopher Wilson, Aaron A Cohen-Gadol, Piiamaria Virtanen, Noah Burket, Matthew Blackwell, Jenna Koenig, Anthony Alfonso, Joseph Davis, Mohamed A Zaazoue, Ghazaleh Tabatabai, Marcos Tatagiba, Felix Behling, Jill S Barnholtz-Sloan, Andrew E Sloan, Silky Chotai, Lola B Chambless, Alireza Mansouri, Felix Ehret, David Capper, Derek S Tsang, Kenneth Aldape, Andrew Gao, Farshad Nassiri, Gelareh Zadeh","doi":"10.1093/neuonc/noae236","DOIUrl":"10.1093/neuonc/noae236","url":null,"abstract":"<p><strong>Background: </strong>We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion since its original publication. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation predictor compatible with newer methylation arrays.</p><p><strong>Methods: </strong>Genome-wide methylation profiles were generated with the Illumina EPICArray. The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. An nomogram was generated by incorporating our methylation predictor with WHO grade and the extent of resection.</p><p><strong>Results: </strong>A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and an external cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperform the 2021 WHO grade in predicting early postoperative recurrence. Dichotomizing patients into grade-specific risk subgroups was predictive of outcomes within both WHO grades 1 and 2 tumors (P < .05), whereas all WHO grade 3 tumors were considered high-risk. Multivariable Cox regression demonstrated the benefit of adjuvant radiotherapy (RT) in high-risk cases specifically, reinforcing its informative role in clinical decision-making. Finally, our next-generation predictor contains nearly 10-fold fewer features than the original model, allowing for targeted arrays.</p><p><strong>Conclusions: </strong>This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms the 2021 WHO grading in predicting time to recurrence. We make this available as a point-and-click tool that will improve prognostication, inform patient selection for RT, and allow for molecularly stratified clinical trials.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1004-1016"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583595","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":"G-quadruplex stabilizer CX-5461 effectively combines with radiotherapy to target α-thalassemia/mental retardation X-linked-deficient malignant glioma.","authors":"Sharvari Dharmaiah, Prit Benny Malgulwar, William E Johnson, Brandon A Chen, Vladislav Sharin, Benjamin T Whitfield, Christian Alvarez, Vasudev Tadimeti, Ahsan S Farooqi, Jason T Huse","doi":"10.1093/neuonc/noae248","DOIUrl":"10.1093/neuonc/noae248","url":null,"abstract":"<p><strong>Background: </strong>Inactivation of α-thalassemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures, enhancing replication stress and genomic instability. Building on earlier work, we evaluated the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in ATRX-deficient preclinical glioma models.</p><p><strong>Methods: </strong>Using the G4 stabilizer CX-5461, we treated patient-derived glioma stem cells (GSCs) in vitro and GSC flank and intracranial murine xenografts in vivo to evaluate efficacy as both a single agent and in combination with ionizing radiation (IR), the latter a central element of current treatment standards.</p><p><strong>Results: </strong>CX-5461 promoted dose-sensitive lethality in ATRX-deficient GSCs relative to ATRX-intact controls. Mechanistic studies revealed that CX-5461 disrupted histone variant H3.3 deposition, enhanced replication stress and DNA damage, activated p53-independent apoptosis, and induced G2/M arrest to a greater extent in ATRX-deficient GSCs than in ATRX-intact counterparts. These data were corroborated in vivo, where CX-5461/IR treatment profoundly delayed tumor growth and prolonged survival in mice bearing ATRX-deficient flank xenografts. Histopathological analyses revealed decreased proliferation, increased apoptosis, and significant G4 induction, replication stress, and DNA damage in CX-5461-treated tumors, both alone and in combination with IR. Finally, despite suboptimal blood-brain-barrier penetration, systemic CX-5461 treatment induced tangible pharmacodynamic effects in ATRX-deficient intracranial GSC models.</p><p><strong>Conclusions: </strong>In totality, our work substantively demonstrates efficacy and defines mechanisms of action for G4 stabilization as a novel therapeutic strategy targeting ATRX-deficient malignant glioma, laying the groundwork for clinical translation.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"932-947"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681613","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":"Canonical amplifications and CDKN2A/B loss refine IDH1/2-mutant astrocytoma prognosis.","authors":"Hia S Ghosh, Ruchit V Patel, Elizabeth B Claus, Luis Nicolas Gonzalez Castro, Patrick Y Wen, Keith L Ligon, David M Meredith, Wenya Linda Bi","doi":"10.1093/neuonc/noae258","DOIUrl":"10.1093/neuonc/noae258","url":null,"abstract":"<p><strong>Background: </strong>Molecular features have been incorporated alongside histologic criteria to improve glioma diagnostics and prognostication. CDKN2A/B homozygous-loss associates with worse survival in IDH1/2-mutant astrocytomas (IDHmut-astrocytomas), the presence of which denotes a grade 4 tumor independent of histologic features. However, no molecular features distinguish survival amongst histologically defined grade 2 and 3 IDHmut-astrocytomas.</p><p><strong>Methods: </strong>We assembled a cohort of patients ≥19 years old diagnosed with an IDHmut-astrocytoma between 1989 and 2020 from public datasets and several academic medical centers. Multivariate modeling and unbiased clustering were used to stratify risk.</p><p><strong>Results: </strong>We identified 998 IDHmut-astrocytoma patients (41.5% female; 85.6% white). Tumor grade, CDKN2A/B loss, and/or ≥1 focal amplification were associated with reduced survival. Grade 2/3 patients with intact CDKN2A/B and no focal amplifications survived the longest (OS 205.7 months). Survival for grade 2/3 cases with either CDKN2A/B hemizygous-loss or focal amplifications (80.4, 88.7 months respectively) did not differ significantly from grade 4 cases with intact CDKN2A/B and no amplifications (91.5 months, P = .93). Grade 4 patients with either hemizygous or homozygous loss of CDKN2A/B had the shortest survival (OS 31.9, 32.5 months respectively), followed by grade 4 cases with intact CDKN2A/B and focal gene amplifications (OS 55.9 months). Integrating CDKN2A/B status and amplifications alongside histopathologic grade refined overall survival prediction. Unbiased clustering revealed 9 distinct molecular profiles, with differential survival. IDHmut-astrocytomas with any CDKN2A/B loss clustered together, regardless of grade, and exhibited the poorest outcomes.</p><p><strong>Conclusions: </strong>Combining CDKN2A/B hemizygous-loss and focal gene amplifications reveals a group of IDHmut-astrocytoma patients with an intermediate prognosis, refining IDHmut-astrocytoma classification.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"993-1003"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709522","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":"Pre-radiation targeted therapy for highly selected patients with newly diagnosed glioblastoma: New tricks for an old dog?","authors":"Macarena I de la Fuente, Andrew B Lassman","doi":"10.1093/neuonc/noaf014","DOIUrl":"10.1093/neuonc/noaf014","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"897-899"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033750","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":"Development and validation of a clinical risk model for postoperative outcome in newly diagnosed glioblastoma: A report of the RANO resect group.","authors":"Philipp Karschnia, Jacob S Young, Gilbert C Youssef, Antonio Dono, Levin Häni, Tommaso Sciortino, Francesco Bruno, Stephanie T Juenger, Nico Teske, Jorg Dietrich, Michael Weller, Michael A Vogelbaum, Martin van den Bent, Juergen Beck, Niklas Thon, Jasper K W Gerritsen, Shawn Hervey-Jumper, Daniel P Cahill, Susan M Chang, Roberta Rudà, Lorenzo Bello, Oliver Schnell, Yoshua Esquenazi, Maximilian I Ruge, Stefan J Grau, Raymond Y Huang, Patrick Y Wen, Mitchel S Berger, Annette M Molinaro, Joerg-Christian Tonn","doi":"10.1093/neuonc/noae231","DOIUrl":"10.1093/neuonc/noae231","url":null,"abstract":"<p><strong>Background: </strong>Following surgery, patients with newly diagnosed glioblastoma frequently enter clinical trials. Nuanced risk assessment is warranted to reduce imbalances between study arms. Here, we aimed (I) to analyze the interactive effects of residual tumor with clinical and molecular factors on outcome and (II) to define a postoperative risk assessment tool.</p><p><strong>Methods: </strong>The response assessment in neuro-oncology (RANO) resect group retrospectively compiled an international, seven-center training cohort of patients with newly diagnosed glioblastoma. The combined associations of residual tumor with molecular or clinical factors and survival were analyzed, and recursive partitioning analysis was performed for risk modeling. The resulting model was prognostically verified in a separate external validation cohort.</p><p><strong>Results: </strong>Our training cohort compromised 1003 patients with newly diagnosed isocitrate dehydrogenase-wildtype glioblastoma. Residual tumor, O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status, age, and postoperative Karnofsky Performance Score were prognostic for survival and incorporated into regression tree analysis. By individually weighting the prognostic factors, an additive score (range, 0-9 points) integrating these four variables distinguished patients with low (0-2 points), intermediate (3-5 points), and high risk (6-9 points) for inferior survival. The prognostic value of our risk model was retained in treatment-based subgroups and confirmed in an external validation cohort of 258 patients with glioblastoma. Compared to previously postulated models, goodness-of-fit measurements were superior for our model.</p><p><strong>Conclusions: </strong>The novel RANO risk model serves as an easy-to-use, yet highly prognostic tool for postoperative patient stratification prior to further therapy. The model may serve to guide patient management and reduce imbalances between study arms in prospective trials.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1046-1060"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569113","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":"A novel nuclear RNA HSD52 scaffolding NONO/SFPQ complex modulates DNA damage repair to facilitate temozolomide resistance.","authors":"Nan Sun, Qun Chen, Hao Chen, Penggang Sun, Yuxiang Liu, Dan Song, Daohan Yu, Pandeng Wang, Yu Song, Jie Qin, Kaifu Tian, Junzhe Zhong, Wenbin Ma, Hanwen Xuan, Da Qian, Ye Yuan, Tongzheng Chen, Xin Wang, Chuanlu Jiang, Jinquan Cai, Xiangqi Meng","doi":"10.1093/neuonc/noae272","DOIUrl":"10.1093/neuonc/noae272","url":null,"abstract":"<p><strong>Background: </strong>Temozolomide (TMZ) is used in the treatment of glioblastoma (GBM). However, the primary obstacle remains the emergence of TMZ chemotherapy resistance. Non-POU domain-containing octamer-binding protein (NONO) and splicing factor proline/glutamine rich (SFPQ) are multifunctional nuclear proteins involved in genome stability and gene regulation. However, the specific role of NONO and SFPQ in TMZ resistance of GBM remains to be explored.</p><p><strong>Methods: </strong>RNA-binding protein immunoprecipitation-microarray and RNA microarray of TMZ-resistant and parental cells were performed for the gain of HSD52. The effects of HSD52 on TMZ resistance were investigated through in vitro assays, intracranial xenograft, and GBM organoid models. The underlying mechanisms were explored by DNA methylation chip, RNA immunoprecipitation, RNA pull-down assays, among others. GBM clinical samples were rolled in to investigate the clinical significance of HSD52.</p><p><strong>Results: </strong>We identified a novel noncoding RNA, HSD52, that was highly expressed in TMZ-resistant GBM and facilitated the interaction between NONO and SFPQ. H3 ubiquitination attenuation and reduced DNA methyltransferase 1 (DNMT1) recruitment increased HSD52 transcription via DNA hypo-methylation. HSD52 formed an RNA duplex with UFM1 specific ligase 1 (UFL1) mRNA, thereby promoting NONO/SFPQ complex binding to UFL1 mRNA and enhancing its stability, and then contributed to TMZ resistance through activating the ataxia telangiectasia mutated signaling pathway. In vivo xenograft and GBM organoid models showed significant repression in tumor growth after HSD52 knockout with TMZ treatment. In GBM clinical samples, HSD52 was responsible for the malignant progression and TMZ resistance.</p><p><strong>Conclusions: </strong>Our results revealed that HSD52 could serve as a promising therapeutic target to overcome TMZ resistance, improving the clinical efficacy of TMZ chemotherapy in GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"963-978"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824460","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":"Phase 2 trial of veliparib, local irradiation, and temozolomide in patients with newly diagnosed high-grade glioma: a Children's Oncology Group study.","authors":"Matthias A Karajannis, Arzu Onar-Thomas, Tong Lin, Patricia A Baxter, Daniel R Boué, Bonnie L Cole, Christine Fuller, Sofia Haque, Nada Jabado, John T Lucas, Shannon M MacDonald, Celeste Matsushima, Namrata Patel, Christopher R Pierson, Mark M Souweidane, Diana L Thomas, Michael F Walsh, Wafik Zaky, Sarah E S Leary, Amar Gajjar, Maryam Fouladi, Kenneth J Cohen","doi":"10.1093/neuonc/noae247","DOIUrl":"10.1093/neuonc/noae247","url":null,"abstract":"<p><strong>Background: </strong>The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy.</p><p><strong>Methods: </strong>We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations, compared to patient-level data from historical cohorts with closely matching clinical and molecular features. Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant).</p><p><strong>Results: </strong>Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year event-free survival (EFS) was 23% (standard error, SE = 9%) and the 1-year overall survival (OS) was 64% (SE = 10%). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year EFS was 57% (SE = 13%) and 1-year OS was 93% (SE = 0.7%).</p><p><strong>Conclusions: </strong>Rapid central pathology review and molecular testing for eligibility were feasible. The protocol therapy including radiation, veliparib, and temozolomide was well tolerated but failed to improve outcomes compared to clinically and molecularly matched historical control cohorts treated with higher doses of alkylator chemotherapy.</p><p><strong>Clinicaltrials.gov identifier: </strong>NCT03581292 (first posted: July 10, 2018).</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1092-1101"},"PeriodicalIF":16.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668032","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":"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}