Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf093
Wenjuan Zhang, Michael P Grams, Rajneet K Oberoi, Ju-Hee Oh, Paul A Decker, Terence T Sio, Surabhi Talele, Zachary C Wilson, Margaret A Connors, Katrina K Bakken, Brett L Carlson, Lauren L Ott, Danielle M Burgenske, Erik J Tryggestad, Jeanette E Eckel Passow, William F Elmquist, Jann N Sarkaria
{"title":"The impact of therapeutic radiation on drug distribution across the blood-brain barrier in normal mouse brain and orthotopic glioblastoma tumors.","authors":"Wenjuan Zhang, Michael P Grams, Rajneet K Oberoi, Ju-Hee Oh, Paul A Decker, Terence T Sio, Surabhi Talele, Zachary C Wilson, Margaret A Connors, Katrina K Bakken, Brett L Carlson, Lauren L Ott, Danielle M Burgenske, Erik J Tryggestad, Jeanette E Eckel Passow, William F Elmquist, Jann N Sarkaria","doi":"10.1093/neuonc/noaf093","DOIUrl":"10.1093/neuonc/noaf093","url":null,"abstract":"<p><strong>Background: </strong>Most oncology therapeutics have limited distribution into the brain, and developing strategies to overcome this limitation would be clinically impactful. While therapeutic radiation is often cited as a strategy to accomplish this, there are no published studies demonstrating the effect of radiation on drug distribution into the brain or brain tumors.</p><p><strong>Methods: </strong>Mice were treated with brain radiation (6 Gy × 5, 4 Gy × 10; 40 Gy × 1) and dosed with drugs (levetiracetam, cefazolin, nedisertib, brigimadlin, apitolisib, or GNE-317) at times ranging from just prior to months after radiation. Plasma and tissue drug concentrations were measured by LC-MS/MS.</p><p><strong>Results: </strong>Radiation did not significantly enhance drug delivery into brain tissue for levetiracetam, cefazolin, GNE-317, apitolisib, or nedisertib at any time post-radiation. Even a single, supra-therapeutic dose of radiation (40 Gy) did not significantly affect brain distribution of GNE-317 or apitolisib (P ≥ .07) from 16 to 160 hours post-radiation. For brigimadlin, radiation (6 Gy × 5) was associated with a modest but significant increase in drug accumulation only at 72 hours post-radiation (brain-to-plasma ratio 0.014 ± 0.006 vs. 0.025 ± 0.010, respectively; P = .04), but not at any other timepoint (24 hours, 15, 28, 94, 133, 183 days; P > .05). Similarly, radiation (6 Gy × 5) of orthotopic tumors did not increase levels of brigimadlin in GBM10 or GBM108 or nedisertib in GBM108 (P > .05).</p><p><strong>Conclusions: </strong>Radiation had no meaningful impact on drug delivery into brain or brain tumors for the drugs tested.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2250-2261"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753428","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}
Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf102
Zhiyi Xue, Ann C Mladek, Sneha Rathi, Sonia Jain, Rachael A Vaubel, Lateef A Odukoya, Darwin A Garcia, Lily Liu, Katrina K Bakken, Brett L Carlson, Lauren L Ott, Danielle M Burgenske, Zeng Hu, Sonja Dragojevic, Paul A Decker, Matthew L Kosel, William G Breen, Shiv K Gupta, Jeanette E Eckel-Passow, William F Elmquist, Wei Zhong, Jann N Sarkaria
{"title":"The novel brain penetrant ataxia-telangiectasia mutated inhibitor WSD0628 provides robust radiosensitization of brain tumor patient-derived xenografts.","authors":"Zhiyi Xue, Ann C Mladek, Sneha Rathi, Sonia Jain, Rachael A Vaubel, Lateef A Odukoya, Darwin A Garcia, Lily Liu, Katrina K Bakken, Brett L Carlson, Lauren L Ott, Danielle M Burgenske, Zeng Hu, Sonja Dragojevic, Paul A Decker, Matthew L Kosel, William G Breen, Shiv K Gupta, Jeanette E Eckel-Passow, William F Elmquist, Wei Zhong, Jann N Sarkaria","doi":"10.1093/neuonc/noaf102","DOIUrl":"10.1093/neuonc/noaf102","url":null,"abstract":"<p><strong>Background: </strong>The ataxia-telangiectasia mutated (ATM) protein coordinates the cellular response to therapeutic radiation, and ATM inhibitors can potentially enhance the efficacy of radiation in otherwise radiation-resistant tumors.</p><p><strong>Methods: </strong>The small molecule ATM kinase inhibitor WSD0628 was specifically designed for enhanced distribution across the blood-brain barrier to more effectively treat glioblastoma (GBM) and brain metastases in combination with radiation therapy (RT). GBM and brain metastasis patient-derived xenograft models were used to understand target inhibition, radiosensitization, inhibition of the DNA damage response, and in vivo efficacy.</p><p><strong>Results: </strong>Initial in vitro characterization of WSD0628 demonstrates a high level of selectivity across kinase families, limited aldehyde oxidase liability, and low risk of hERG interactions. Consistent with a central role for ATM in radiation response, WSD0628 blocked radiation-induced signaling and enhanced radiosensitivity in U251 glioma cells and brain tumor PDXs GBM120 and M12. In comparison to control or RT alone in orthotopic PDXs, the combination of WSD0628 with RT markedly prolonged median survival-GBM12 (19, 55, and 408 days, respectively); GBM43 (26, 44, and 143 days, respectively); GBM120 (51, 89, and 231 days, respectively); M12 (17, 39, and 190 days, respectively). Pharmacokinetic and pharmacodynamic testing after treatment in orthotopic GBM43 tumors showed inhibitory levels of WSD0628 and a reduction of γH2AX foci in the combination-treated tumors.</p><p><strong>Conclusions: </strong>Collectively, these results suggest a promising role for WSD0628 in combination with RT in brain tumors and provide the rationale for an ongoing Phase 0/1A clinical trial testing this combination in recurrent GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2313-2325"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005908","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}
Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf106
David Hou, Si Wang, Brandyn A Castro, Joshua L Katz, Mark Dapash, Victor A Arrieta, Gustavo I Vazquez-Cervantes, Hanxiao Wan, Leah K Billingham, Rebecca Du, Alina R Murphy, Aurora Lopez-Rosas, Yu Han, Ronit V Patel, Tzu-Yi Chia, Crismita C Dmello, Peng Zhang, Dean Sheppard, Adam M Sonabend, Jason M Miska, Maciej S Lesniak, Dieter Henrik Heiland, Catalina Lee-Chang
{"title":"Dual aVß8 Integrin and PD-1 Blockade Overcomes TGFβ-Mediated B-Cell Suppression to Enhance Anti-Tumor Immunity.","authors":"David Hou, Si Wang, Brandyn A Castro, Joshua L Katz, Mark Dapash, Victor A Arrieta, Gustavo I Vazquez-Cervantes, Hanxiao Wan, Leah K Billingham, Rebecca Du, Alina R Murphy, Aurora Lopez-Rosas, Yu Han, Ronit V Patel, Tzu-Yi Chia, Crismita C Dmello, Peng Zhang, Dean Sheppard, Adam M Sonabend, Jason M Miska, Maciej S Lesniak, Dieter Henrik Heiland, Catalina Lee-Chang","doi":"10.1093/neuonc/noaf106","DOIUrl":"10.1093/neuonc/noaf106","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy has revolutionized cancer treatment but has yet to be translated into brain tumors. Studies in other solid tumors suggest a central role of B-cell immunity in driving immune checkpoint blockade efficacy. In glioblastoma (GBM), tumor B cells are driven into a regulatory B-cell state that suppresses immune activation and T-cell function.</p><p><strong>Methods: </strong>We used spatially resolved transcriptomics and multiplex immunofluorescence to characterize B-cell neighborhoods within GBM and identify enhanced TGFβ-signaling between myeloid and B cells. We generated conditional knockouts to investigate the effects of TGFβ signaling on B-cell function and survival in vivo. Additionally, we combined TGFβ blockade with PD-1 inhibition to evaluate their combined anti-glioma efficacy.</p><p><strong>Results: </strong>Our findings reveal that myeloid cells are the primary interactors with B cells in GBM through the TGFβ pathway. Pharmacological or genetic TGFβ blockade expanded intratumoral B cells and synergized with PD-1 inhibition to enhance survival (60% tumor eradication in dual-treated mice). Therapeutic efficacy critically depended on B cells, as their depletion abolished survival benefits. Dual αVβ8/PD-1 blockade reduced B-cell-mediated suppression of CD8⁺ T-cell cytotoxicity and increased plasmablast differentiation, while partial efficacy in RagKO mice implicated ancillary roles for innate immunity.</p><p><strong>Conclusion: </strong>Targeting TGFβ signaling using an anti-αVβ8 blocker can impact anti-tumor immunity through different possible mechanisms, of which we highlight the rescuing of B-cell function through synergy with PD-1 checkpoint blockade therapy. Our work underscores the critical role of intratumoral B-cell immunity in enhancing immunotherapy against brain tumors.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2355-2369"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022641","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}
Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf073
Heather M Conklin, Nicole A Salman, Johnnie K Bass, Jie Huang, Arzu Onar-Thomas, Jason M Ashford, Jennifer Harman, Jeanelle S Ali, Michelle A Swain, Lana L Harder, Bonnie L Carlson-Green, Jonathan M Miller, Joanna Wallace, Ryan J Kaner, Thomas E Merchant, Giles W Robinson, Amar Gajjar
{"title":"Ototoxicity and cognitive outcomes among very young children treated for brain tumors: Findings from a multisite, prospective, longitudinal trial.","authors":"Heather M Conklin, Nicole A Salman, Johnnie K Bass, Jie Huang, Arzu Onar-Thomas, Jason M Ashford, Jennifer Harman, Jeanelle S Ali, Michelle A Swain, Lana L Harder, Bonnie L Carlson-Green, Jonathan M Miller, Joanna Wallace, Ryan J Kaner, Thomas E Merchant, Giles W Robinson, Amar Gajjar","doi":"10.1093/neuonc/noaf073","DOIUrl":"10.1093/neuonc/noaf073","url":null,"abstract":"<p><strong>Background: </strong>Brain tumor treatment can result in sensorineural hearing loss (SNHL) that is associated with cognitive declines in school-age children. Young children treated for brain tumors are at heightened cognitive risk. This study examines the unique contribution of treatment-related ototoxicity to cognitive outcomes in young children treated for brain tumors.</p><p><strong>Methods: </strong>135 young children (mean age = 1.7 years) with a newly diagnosed malignant brain tumor were treated with chemotherapy, with or without focal proton or photon radiation therapy. Serial audiology and neurocognitive assessments were conducted for 5 years as part of a prospective, multisite, longitudinal trial (SJYC07; NCT00602667). SNHL was dichotomized as present versus not present (Chang grade ≥1a vs. 0). Neurocognitive assessments included intellectual functioning and parent ratings of adaptive functioning and attention.</p><p><strong>Results: </strong>67% of patients experienced mild-to-severe SNHL, which was associated with younger age at diagnosis (P < .001) but not sex, treatment, or study risk arm (P > .10). Pre-treatment, higher intelligence quotient (IQ) was associated with older age and higher socioeconomic status (P < .01), with a negative change in IQ trajectory after SNHL that was worse for children with supratentorial tumors. Pre-treatment, higher adaptive functioning was associated with older age (P = .0001), with a negative change in adaptive functioning trajectory after SNHL that was worse for those treated at a younger age. Attention problems increased after SNHL for the entire group (P = .0099).</p><p><strong>Conclusions: </strong>SNHL is associated with IQ decline and worsening adaptive functioning and attention in young children treated for brain tumors. These findings have important implications for treatment modifications, interventions, and caregiver education.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2461-2471"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692953","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}
Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf134
Mackenzie Price, Justin T Low, Gordon Chavez, Patrick Conlon, Nick Avgeropoulos, Carol Kruchko, Gino Cioffi, Kristin A Waite, Jill S Barnholtz-Sloan, Quinn T Ostrom
{"title":"Improvements in survival for glioblastoma in the post-Stupp protocol era.","authors":"Mackenzie Price, Justin T Low, Gordon Chavez, Patrick Conlon, Nick Avgeropoulos, Carol Kruchko, Gino Cioffi, Kristin A Waite, Jill S Barnholtz-Sloan, Quinn T Ostrom","doi":"10.1093/neuonc/noaf134","DOIUrl":"10.1093/neuonc/noaf134","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2484-2486"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691102","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}
Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf131
Zachary C Gersey, Serafettin Zenkin, Priyadarshini Mamindla, Mohammadreza Amjadzadeh, Murat Ak, Tritan Plute, Vishal Peddagangireddy, Hussein Abdallah, Nallammai Muthiah, Eric W Wang, Carl Snyderman, Paul A Gardner, Rivka R Colen, Georgios A Zenonos
{"title":"Radiogenomics and radiomics of skull base chordoma: Classification of novel radiomic subgroups and prediction of genetic signatures and clinical outcomes.","authors":"Zachary C Gersey, Serafettin Zenkin, Priyadarshini Mamindla, Mohammadreza Amjadzadeh, Murat Ak, Tritan Plute, Vishal Peddagangireddy, Hussein Abdallah, Nallammai Muthiah, Eric W Wang, Carl Snyderman, Paul A Gardner, Rivka R Colen, Georgios A Zenonos","doi":"10.1093/neuonc/noaf131","DOIUrl":"10.1093/neuonc/noaf131","url":null,"abstract":"<p><strong>Background: </strong>Chordomas are rare, aggressive tumors of notochordal origin, commonly affecting the spine and skull base. Skull base chordomas (SBCs) comprise approximately 39% of cases, with an incidence of less than 1 per million annually in the United States. Prognosis remains poor due to resistance to chemotherapy, often requiring extensive surgical resection and adjuvant radiotherapy. Current classification methods based on chromosomal deletions are invasive and costly, presenting a need for alternative diagnostic tools. Radiomics allows for noninvasive SBC diagnosis and treatment planning.</p><p><strong>Methods: </strong>We developed and validated radiomic-based models using MRI data to predict overall survival (OS) and progression-free survival following surgery (PFSS) in SBC patients. Machine-learning classifiers, including eXtreme Gradient Boosting (XGBoost), were employed along with feature selection techniques. Unsupervised clustering identified radiomic-based subgroups, which were correlated with chromosomal deletions and clinical outcomes.</p><p><strong>Results: </strong>Our XGBoost model demonstrated superior predictive performance, achieving an area under the curve (AUC) of 83.33% for OS and 80.36% for PFSS, outperforming other classifiers. Radiomic clustering revealed two SBC groups with differing survival and molecular characteristics, strongly correlating with chromosomal deletion profiles. These findings indicate that radiomics can noninvasively characterize SBC phenotypes and stratify patients by prognosis.</p><p><strong>Conclusions: </strong>Radiomics shows promise as a reliable, noninvasive tool for the prognostication and classification of SBCs, minimizing the need for invasive genetic testing and supporting personalized treatment strategies.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2472-2483"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199659","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}
Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf112
Takahide Nejo, Robert M Prins, Hideho Okada
{"title":"The T-cell receptor repertoire: A window into pediatric brain tumor immunity.","authors":"Takahide Nejo, Robert M Prins, Hideho Okada","doi":"10.1093/neuonc/noaf112","DOIUrl":"10.1093/neuonc/noaf112","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2207-2208"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064315","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}
Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf099
Chia-Yang Hung, Elaine Y Kang, Karol Jacek, Chunsong Yu, Xiaowei Zhang, Yicheng Zhu, Maryam Aftabizadeh, Robyn A Wong, Benham Badie, Piotr Świderski, Bożena Kamińska, Darya Alizadeh, Amy B Heimberger, Christine E Brown, Marcin Kortylewski
{"title":"Multimodal glioma immunotherapy combining TLR9-targeted STAT3 antisense oligodeoxynucleotides with PD1 immune checkpoint blockade.","authors":"Chia-Yang Hung, Elaine Y Kang, Karol Jacek, Chunsong Yu, Xiaowei Zhang, Yicheng Zhu, Maryam Aftabizadeh, Robyn A Wong, Benham Badie, Piotr Świderski, Bożena Kamińska, Darya Alizadeh, Amy B Heimberger, Christine E Brown, Marcin Kortylewski","doi":"10.1093/neuonc/noaf099","DOIUrl":"10.1093/neuonc/noaf099","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic resistance in glioblastoma (GBM) is multifactorial and results from genetic heterogeneity, the immunoprivileged localization, and the potently tolerogenic microenvironment. Signal transducer and activator of transcription 3 (STAT3) plays a key role in both glioma cell survival and immune evasion, reinforcing GBM resistance.</p><p><strong>Methods: </strong>Here, we describe a new cell-selective and double-stranded STAT3 antisense oligonucleotide (CpG-STAT3dsASO) for targeting human/mouse glioma cells and GAMs but not T cells. The oligonucleotide safety and efficacy against orthotopic GBM was assessed in immunocompetent or immunodeficient mice.</p><p><strong>Results: </strong>CpG-STAT3dsASO injected intracranially/intratumorally was well-tolerated and reduced progression of human U251 GBM xenotransplants and mouse GL261 or neural cell-derived QPP8 gliomas. Unlike the single-stranded oligonucleotide, local CpG-STAT3dsASO administration did not trigger type-I IFN-dependent neurotoxicities in immunocompetent mice within the therapeutic dose range. CpG-STAT3dsASO activated intratumoral GAMs, such as dendritic cells, macrophages and microglia, thereby expanding CD4+ Th1 cells while reducing TREG numbers. CpG-STAT3dsASO monotherapy did not have curative effects as it led to recruitment of only limited numbers of mostly exhausted effector CD8+ T cells. However, when combined with systemic PD1 inhibition, CpG-STAT3dsASO/anti-PD1 treatments caused regression of GL261 as well as immunotherapy-resistant QPP8 gliomas and resulted in long-term survival of the majority of mice. The combination treatment boosted CD8+ effector T-cell activity, while promoting their intratumoral interaction with activated CD4+ Th1 cells and activated macrophages as indicated by spatial transcriptomics.</p><p><strong>Conclusions: </strong>Our results suggest rationale for GBM immunotherapy using CpG-STAT3dsASO to disrupt GAMs-dependent immune evasion, thereby restoring sensitivity to PD1 blockade and facilitating T-cell-mediated antitumor immune responses.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2296-2312"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003237","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}
Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf075
Zhiwei Xue, Xuehai Zhang, Bo Mao, Guangjing Mu, Yan Zhang, Junzhi Liu, Jiangli Zhao, Xuchen Liu, Yanfei Sun, Guo Xiang, Hongwei Wang, Wenzhe Xu, Zheng Jiang, Shuai Wang, Rolf Bjerkvig, Jian Wang, Donghai Wang, Xingang Li, Bin Huang, Mingzhi Han
{"title":"Dual role of WNT10A in promoting the malignancy of glioblastoma and remodeling the tumor microenvironment.","authors":"Zhiwei Xue, Xuehai Zhang, Bo Mao, Guangjing Mu, Yan Zhang, Junzhi Liu, Jiangli Zhao, Xuchen Liu, Yanfei Sun, Guo Xiang, Hongwei Wang, Wenzhe Xu, Zheng Jiang, Shuai Wang, Rolf Bjerkvig, Jian Wang, Donghai Wang, Xingang Li, Bin Huang, Mingzhi Han","doi":"10.1093/neuonc/noaf075","DOIUrl":"10.1093/neuonc/noaf075","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) represents a complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Here, we show that WNT10A, a member of the WNT family, plays an important role in GBM growth where its influence is mediated via both autocrine and paracrine pathways thereby stimulating not only the tumor cells but also normal cell types within the tumor microenvironment (TME).</p><p><strong>Methods: </strong>In silico analysis was performed to identify high-expressing WNT family members in GBM. Knockdown and overexpression methods were used to examine the function of WNT10A in GBM cells and in orthotopic GBM xenografts in vivo. Co-immunoprecipitation (Co-IP) was used to confirm receptor binding and chromatin immunoprecipitation (ChIP) was performed to analyze transcriptional activation of downstream genes.</p><p><strong>Results: </strong>WNT10A was found to be highly expressed in GBMs and its knockdown significantly suppressed GBM malignant behavior in vitro and in vivo. Co-IP assays confirmed an interaction between WNT10A and FZD1, which activated the JNK/c-Jun/FOSB signaling pathway and enhanced the transcription of FOSB. Importantly, GBM cells secreted WNT10A into the tumor microenvironment, leading to an activation of the PI3K-AKT pathway in tumor-associated macrophages (TAMs) and the JNK pathway in tumor-associated astrocytes. The latter caused a secretion of tumor-promoting cytokines IL-6, MCP-1, and angiogenin. LGK974, a PORCN inhibitor, inhibited the secretion of WNT10A to suppress the malignant GBM phenotype.</p><p><strong>Conclusions: </strong>Our findings revealed that WNT10A is a critical factor in promoting GBM progression through both autocrine and paracrine mechanisms. Thus, our findings provide the foundation for WNT-targeted clinical GBM treatment.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2232-2249"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658057","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}
Neuro-oncologyPub Date : 2025-10-14DOI: 10.1093/neuonc/noaf133
Aleksandra B Lasica, Zhou Lan, Julie J Miller, Albert Jiao, Ian Pan, Loai Aker, Prem Prabhakar, Julia Japo, Alyssa Russ, Catharina Westergaard, Elisa Aquilanti, Ugonma Chukwueke, L Nicolas Gonzalez Castro, J Ricardo McFaline Figueroa, Eudocia Quant Lee, Lakshmi Nayak, Rameen Beroukhim, Tracy T Batchelor, Daniel P Cahill, Vihang Nakhate, Tyler Lanman, Juan Pablo Ospina, Natalie Stec, Ruchit V Patel, David M Meredith, Wenya Linda Bi, David A Reardon, Keith L Ligon, Raymond Y Huang, Patrick Y Wen, Gilbert Youssef
{"title":"Clinical, molecular, and radiological predictors of prognosis in newly diagnosed astrocytoma, IDH-mutant, WHO grade 4.","authors":"Aleksandra B Lasica, Zhou Lan, Julie J Miller, Albert Jiao, Ian Pan, Loai Aker, Prem Prabhakar, Julia Japo, Alyssa Russ, Catharina Westergaard, Elisa Aquilanti, Ugonma Chukwueke, L Nicolas Gonzalez Castro, J Ricardo McFaline Figueroa, Eudocia Quant Lee, Lakshmi Nayak, Rameen Beroukhim, Tracy T Batchelor, Daniel P Cahill, Vihang Nakhate, Tyler Lanman, Juan Pablo Ospina, Natalie Stec, Ruchit V Patel, David M Meredith, Wenya Linda Bi, David A Reardon, Keith L Ligon, Raymond Y Huang, Patrick Y Wen, Gilbert Youssef","doi":"10.1093/neuonc/noaf133","DOIUrl":"10.1093/neuonc/noaf133","url":null,"abstract":"<p><strong>Background: </strong>Astrocytoma, isocitrate dehydrogenase-mutant, WHO grade 4 (Astro4), is a new tumor type in the 2021 WHO classification of central nervous system tumors that has been poorly characterized in the literature. This study evaluates predictors of prognosis in a large cohort of newly diagnosed Astro4.</p><p><strong>Methods: </strong>We retrospectively identified 128 consecutive adult patients who presented with an initial diagnosis of Astro4 at Dana-Farber Cancer Institute and Massachusetts General Hospital between 2010 and 2021. Clinical, molecular, and radiological characteristics were recorded, and their associations with overall survival (OS) and progression-free survival (PFS) were measured by log-rank test and Cox proportional hazards model.</p><p><strong>Results: </strong>The median age at diagnosis was 37.1 years, and 61.7% were men. The median OS was 5.9 years (95% confidence interval, 4.4-7.3), while the median PFS was 2.7 years (1.8 -3.6). Age ≥ 50 and homozygous CDKN2A/B deletion were independent negative prognosticators of OS on univariate and multivariate analyses (hazard ratio [HR], 2.21 [1.16-4.21], P = .019; HR, 2.61 [1.27-5.38], P = .013). Maximal resection of enhancing disease was associated with longer PFS on univariate and multivariate analyses (HR, 0.48 [0.26-0.87], P = .019). There were no significant differences in OS or PFS based on MGMT promoter methylation status, T2/FLAIR extent of resection, T2/FLAIR mismatch, radiological pseudoprogression, or enhancement on the pre-operative scan.</p><p><strong>Conclusions: </strong>Our study comprehensively characterizes a large cohort of newly diagnosed patients with Astro4, emphasizing the prognostic value of CDKN2A/B deletion, age, and the extent of resection of enhancing disease in these patients.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"2382-2398"},"PeriodicalIF":13.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181635","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}