Background: The high fatality rate of glioblastoma (GBM) is attributed to glioblastoma stem cells (GSCs), which exhibit heterogeneity and therapeutic resistance. Metabolic plasticity of mitochondria is the hallmark of GSCs. Targeting mitochondrial biogenesis of GSCs is crucial for improving clinical prognosis in GBM patients.
Methods: SMYD2-induced PGC1α methylation and followed nuclear export are confirmed by co-immunoprecipitation, cellular fractionation, and immunofluorescence. The effects of SMYD2/PGC1α/CRM1 axis on GSCs mitochondrial biogenesis are validated by oxygen consumption rate, ECAR, and intracranial glioma model.
Results: PGC1α methylation causes the disabled mitochondrial function to maintain the stemness, thereby enhancing the radio-resistance of GSCs. SMYD2 drives PGC1α K224 methylation (K224me), which is essential for promoting the stem-like characteristics of GSCs. PGC1α K224me is preferred binding with CRM1, accelerating PGC1α nuclear export and subsequent dysfunction. Targeting PGC1α methylation exhibits significant radiotherapeutic efficacy and prolongs patient survival.
Conclusions: These findings unveil a novel regulatory pathway involving mitochondria that govern stemness in GSCs, thereby emphasizing promising therapeutic strategies targeting PGC1α and mitochondria for the treatment of GBM.
{"title":"SMYD2 induced PGC1α methylation promotes stemness maintenance of glioblastoma stem cells.","authors":"Mengdie Li, Zhixiang Zhang, Liuguijie He, Xiefeng Wang, Jianxing Yin, Xiuxing Wang, Yongping You, Xu Qian, Xin Ge, Zhumei Shi","doi":"10.1093/neuonc/noae090","DOIUrl":"10.1093/neuonc/noae090","url":null,"abstract":"<p><strong>Background: </strong>The high fatality rate of glioblastoma (GBM) is attributed to glioblastoma stem cells (GSCs), which exhibit heterogeneity and therapeutic resistance. Metabolic plasticity of mitochondria is the hallmark of GSCs. Targeting mitochondrial biogenesis of GSCs is crucial for improving clinical prognosis in GBM patients.</p><p><strong>Methods: </strong>SMYD2-induced PGC1α methylation and followed nuclear export are confirmed by co-immunoprecipitation, cellular fractionation, and immunofluorescence. The effects of SMYD2/PGC1α/CRM1 axis on GSCs mitochondrial biogenesis are validated by oxygen consumption rate, ECAR, and intracranial glioma model.</p><p><strong>Results: </strong>PGC1α methylation causes the disabled mitochondrial function to maintain the stemness, thereby enhancing the radio-resistance of GSCs. SMYD2 drives PGC1α K224 methylation (K224me), which is essential for promoting the stem-like characteristics of GSCs. PGC1α K224me is preferred binding with CRM1, accelerating PGC1α nuclear export and subsequent dysfunction. Targeting PGC1α methylation exhibits significant radiotherapeutic efficacy and prolongs patient survival.</p><p><strong>Conclusions: </strong>These findings unveil a novel regulatory pathway involving mitochondria that govern stemness in GSCs, thereby emphasizing promising therapeutic strategies targeting PGC1α and mitochondria for the treatment of GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899034","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}
Leilei Zhou, Niek van Bree, Lola Boutin, Jinhye Ryu, Simon Moussaud, Mingzhi Liu, Magdalena Otrocka, Magnus Olsson, Anna Falk, Margareta Wilhelm
Background: Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current treatments have increased overall survival but can lead to devastating side effects and late complications in survivors, emphasizing the need for new, improved targeted therapies that specifically eliminate tumor cells while sparing the normally developing brain.
Methods: Here, we used a sonic hedgehog (SHH)-MB model based on a patient-derived neuroepithelial stem cell system for an unbiased high-throughput screen with a library of 172 compounds with known targets. Compounds were evaluated in both healthy neural stem cells (NSCs) and tumor cells derived from the same patient. Based on the difference of cell viability and drug sensitivity score between normal cells and tumor cells, hit compounds were selected and further validated in vitro and in vivo.
Results: We identified PF4708671 (S6K1 inhibitor) as a potential agent that selectively targets SHH-driven MB tumor cells while sparing NSCs and differentiated neurons. Subsequent validation studies confirmed that PF4708671 inhibited the growth of SHH-MB tumor cells both in vitro and in vivo, and that knockdown of S6K1 resulted in reduced tumor formation.
Conclusions: Overall, our results suggest that inhibition of S6K1 specifically affects tumor growth, whereas it has less effect on non-tumor cells. Our data also show that the NES cell platform can be used to identify potentially effective new therapies and targets for SHH-MB.
{"title":"High-throughput neural stem cell-based drug screening identifies S6K1 inhibition as a selective vulnerability in sonic hedgehog-medulloblastoma.","authors":"Leilei Zhou, Niek van Bree, Lola Boutin, Jinhye Ryu, Simon Moussaud, Mingzhi Liu, Magdalena Otrocka, Magnus Olsson, Anna Falk, Margareta Wilhelm","doi":"10.1093/neuonc/noae104","DOIUrl":"10.1093/neuonc/noae104","url":null,"abstract":"<p><strong>Background: </strong>Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current treatments have increased overall survival but can lead to devastating side effects and late complications in survivors, emphasizing the need for new, improved targeted therapies that specifically eliminate tumor cells while sparing the normally developing brain.</p><p><strong>Methods: </strong>Here, we used a sonic hedgehog (SHH)-MB model based on a patient-derived neuroepithelial stem cell system for an unbiased high-throughput screen with a library of 172 compounds with known targets. Compounds were evaluated in both healthy neural stem cells (NSCs) and tumor cells derived from the same patient. Based on the difference of cell viability and drug sensitivity score between normal cells and tumor cells, hit compounds were selected and further validated in vitro and in vivo.</p><p><strong>Results: </strong>We identified PF4708671 (S6K1 inhibitor) as a potential agent that selectively targets SHH-driven MB tumor cells while sparing NSCs and differentiated neurons. Subsequent validation studies confirmed that PF4708671 inhibited the growth of SHH-MB tumor cells both in vitro and in vivo, and that knockdown of S6K1 resulted in reduced tumor formation.</p><p><strong>Conclusions: </strong>Overall, our results suggest that inhibition of S6K1 specifically affects tumor growth, whereas it has less effect on non-tumor cells. Our data also show that the NES cell platform can be used to identify potentially effective new therapies and targets for SHH-MB.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301142","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}
Keaton Piper, Jay I Kumar, Joseph Domino, Chad Tuchek, Michael A Vogelbaum
Drug delivery to the central nervous system (CNS) has been a major challenge for CNS tumors due to the impermeability of the blood-brain barrier (BBB). There has been a multitude of techniques aimed at overcoming the BBB obstacle aimed at utilizing natural transport mechanisms or bypassing the BBB which we review here. Another approach that has generated recent interest in the recently published literature is to use new technologies (Laser Interstitial Thermal Therapy, LITT; or Low-Intensity Focused Ultrasound, LIFU) to temporarily increase BBB permeability. This review overviews the advantages, disadvantages, and major advances of each method. LIFU has been a major area of research to allow for chemotherapeutics to cross the BBB which has a particular emphasis in this review. While most of the advances remain in animal studies, there are an increasing number of translational clinical trials that will have results in the next few years.
{"title":"Consensus review on strategies to improve delivery across the blood-brain barrier including focused ultrasound.","authors":"Keaton Piper, Jay I Kumar, Joseph Domino, Chad Tuchek, Michael A Vogelbaum","doi":"10.1093/neuonc/noae087","DOIUrl":"10.1093/neuonc/noae087","url":null,"abstract":"<p><p>Drug delivery to the central nervous system (CNS) has been a major challenge for CNS tumors due to the impermeability of the blood-brain barrier (BBB). There has been a multitude of techniques aimed at overcoming the BBB obstacle aimed at utilizing natural transport mechanisms or bypassing the BBB which we review here. Another approach that has generated recent interest in the recently published literature is to use new technologies (Laser Interstitial Thermal Therapy, LITT; or Low-Intensity Focused Ultrasound, LIFU) to temporarily increase BBB permeability. This review overviews the advantages, disadvantages, and major advances of each method. LIFU has been a major area of research to allow for chemotherapeutics to cross the BBB which has a particular emphasis in this review. While most of the advances remain in animal studies, there are an increasing number of translational clinical trials that will have results in the next few years.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071523","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}
Gunther Nussbaumer, Martin Benesch, Yura Grabovska, Alan Mackay, David Castel, Jacques Grill, Marta M Alonso, Manila Antonelli, Simon Bailey, Joshua N Baugh, Veronica Biassoni, Mirjam Blattner-Johnson, Alberto Broniscer, Andrea Carai, Giovanna Stefania Colafati, Niclas Colditz, Selim Corbacioglu, Shauna Crampsie, Natacha Entz-Werle, Matthias Eyrich, Lea L Friker, Michael C Frühwald, Maria Luisa Garrè, Nicolas U Gerber, Felice Giangaspero, Maria J Gil-da-Costa, Norbert Graf, Darren Hargrave, Peter Hauser, Ulrich Herrlinger, Marion Hoffmann, Esther Hulleman, Elisa Izquierdo, Sandra Jacobs, Michael Karremann, Antonis Kattamis, Rejin Kebudi, Rolf-Dieter Kortmann, Robert Kwiecien, Maura Massimino, Angela Mastronuzzi, Evelina Miele, Giovanni Morana, Claudia M Noack, Virve Pentikainen, Thomas Perwein, Stefan M Pfister, Torsten Pietsch, Kleoniki Roka, Sabrina Rossi, Stefan Rutkowski, Elisabetta Schiavello, Clemens Seidel, Jaroslav Štěrba, Dominik Sturm, David Sumerauer, Anna Tacke, Sara Temelso, Chiara Valentini, Dannis van Vuurden, Pascale Varlet, Sophie E M Veldhuijzen van Zanten, Maria Vinci, André O von Bueren, Monika Warmuth-Metz, Pieter Wesseling, Maria Wiese, Johannes E A Wolff, Josef Zamecnik, Andrés Morales La Madrid, Brigitte Bison, Gerrit H Gielen, David T W Jones, Chris Jones, Christof M Kramm
Background: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established.
Methods: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization.
Results: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS.
Conclusions: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).
{"title":"Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.","authors":"Gunther Nussbaumer, Martin Benesch, Yura Grabovska, Alan Mackay, David Castel, Jacques Grill, Marta M Alonso, Manila Antonelli, Simon Bailey, Joshua N Baugh, Veronica Biassoni, Mirjam Blattner-Johnson, Alberto Broniscer, Andrea Carai, Giovanna Stefania Colafati, Niclas Colditz, Selim Corbacioglu, Shauna Crampsie, Natacha Entz-Werle, Matthias Eyrich, Lea L Friker, Michael C Frühwald, Maria Luisa Garrè, Nicolas U Gerber, Felice Giangaspero, Maria J Gil-da-Costa, Norbert Graf, Darren Hargrave, Peter Hauser, Ulrich Herrlinger, Marion Hoffmann, Esther Hulleman, Elisa Izquierdo, Sandra Jacobs, Michael Karremann, Antonis Kattamis, Rejin Kebudi, Rolf-Dieter Kortmann, Robert Kwiecien, Maura Massimino, Angela Mastronuzzi, Evelina Miele, Giovanni Morana, Claudia M Noack, Virve Pentikainen, Thomas Perwein, Stefan M Pfister, Torsten Pietsch, Kleoniki Roka, Sabrina Rossi, Stefan Rutkowski, Elisabetta Schiavello, Clemens Seidel, Jaroslav Štěrba, Dominik Sturm, David Sumerauer, Anna Tacke, Sara Temelso, Chiara Valentini, Dannis van Vuurden, Pascale Varlet, Sophie E M Veldhuijzen van Zanten, Maria Vinci, André O von Bueren, Monika Warmuth-Metz, Pieter Wesseling, Maria Wiese, Johannes E A Wolff, Josef Zamecnik, Andrés Morales La Madrid, Brigitte Bison, Gerrit H Gielen, David T W Jones, Chris Jones, Christof M Kramm","doi":"10.1093/neuonc/noae080","DOIUrl":"10.1093/neuonc/noae080","url":null,"abstract":"<p><strong>Background: </strong>The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established.</p><p><strong>Methods: </strong>We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization.</p><p><strong>Results: </strong>Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS.</p><p><strong>Conclusions: </strong>Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876957","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}
Patrick Roth, Thierry Gorlia, Jaap C Reijneveld, Filip de Vos, Ahmed Idbaih, Jean-Sébastien Frenel, Emilie Le Rhun, Juan Manuel Sepulveda, James Perry, G Laura Masucci, Pierre Freres, Hal Hirte, Clemens Seidel, Annemiek Walenkamp, Slavka Lukacova, Paul Meijnders, Andre Blais, Francois Ducray, Vincent Verschaeve, Garth Nicholas, Carmen Balana, Daniela A Bota, Matthias Preusser, Sarah Nuyens, Fréderic Dhermain, Martin van den Bent, Chris J O'Callaghan, Maureen Vanlancker, Warren Mason, Michael Weller
Background: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier.
Methods: European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors.
Results: The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm.
Conclusions: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.
背景:新诊断胶质母细胞瘤患者的标准治疗包括手术、放射治疗(RT)和替莫唑胺(TMZ)化疗(TMZ/RT→TMZ)。蛋白酶体是肿瘤细胞的核心生物枢纽,因此一直被认为是一个很有前景的治疗靶点。Marizomib是一种新型泛蛋白酶体抑制剂,可透过血脑屏障:EORTC 1709/CCTG CE.8 是一项多中心、随机对照、开放标签的 3 期优效试验。主要资格标准包括新确诊的胶质母细胞瘤、年龄大于 18 岁、卡诺夫斯基表现状态大于 70。患者按1:1的比例随机分组。主要目的是比较在TMZ/RT→TMZ基础上接受马利佐米治疗的患者与仅接受标准治疗的患者的总生存期(OS):该试验在欧洲、加拿大和美国的 82 家机构展开。共有749名患者(占计划人数750人的99.9%)接受了随机治疗。标准治疗组和马利佐米治疗组的OS无差异(中位17个月 vs 16.5个月;HR=1.04;P=0.64)。PFS 也没有统计学差异(中位 6.0 个月 vs. 6.3 个月;HR=0.97;p=0.67)。在MGMT启动子未甲基化肿瘤患者中,标准疗法和马利佐米的OS也没有差异(中位14.5个月 vs 15.1个月,HR=1.13;P=0.27)。与标准治疗组相比,马利佐米治疗组出现了更多的CTCAE 3/4级治疗突发不良事件:结论:在以替莫唑胺为基础的标准放化疗中加入马利佐米会导致更多毒性,但不会改善新诊断胶质母细胞瘤患者的OS或PFS。
{"title":"Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial.","authors":"Patrick Roth, Thierry Gorlia, Jaap C Reijneveld, Filip de Vos, Ahmed Idbaih, Jean-Sébastien Frenel, Emilie Le Rhun, Juan Manuel Sepulveda, James Perry, G Laura Masucci, Pierre Freres, Hal Hirte, Clemens Seidel, Annemiek Walenkamp, Slavka Lukacova, Paul Meijnders, Andre Blais, Francois Ducray, Vincent Verschaeve, Garth Nicholas, Carmen Balana, Daniela A Bota, Matthias Preusser, Sarah Nuyens, Fréderic Dhermain, Martin van den Bent, Chris J O'Callaghan, Maureen Vanlancker, Warren Mason, Michael Weller","doi":"10.1093/neuonc/noae053","DOIUrl":"10.1093/neuonc/noae053","url":null,"abstract":"<p><strong>Background: </strong>Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier.</p><p><strong>Methods: </strong>European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors.</p><p><strong>Results: </strong>The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm.</p><p><strong>Conclusions: </strong>Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158658","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}
Ophélie Renoult, Mélanie Laurent-Blond, Hala Awada, Lisa Oliver, Noémie Joalland, Mikaël Croyal, François Paris, Catherine Gratas, Claire Pecqueur
Background: Glioblastoma (GBM) is a highly aggressive tumor with unmet therapeutic needs, which can be explained by extensive intra-tumoral heterogeneity and plasticity. In this study, we aimed to investigate the specific metabolic features of Glioblastoma stem cells (GSC), a rare tumor subpopulation involved in tumor growth and therapy resistance.
Methods: We conducted comprehensive analyses of primary patient-derived GBM cultures and GSC-enriched cultures of human GBM cell lines using state-of-the-art molecular, metabolic, and phenotypic studies.
Results: We showed that GSC-enriched cultures display distinct glycolytic profiles compared with differentiated tumor cells. Further analysis revealed that GSC relies on pyruvate carboxylase (PC) activity for survival and self-renewal capacity. Interestingly, inhibition of PC led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of PC restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models.
Conclusions: Our findings demonstrate the critical role of PC in GSC metabolism, survival, and escape to etoposide. They also highlight PC as a therapeutic target to overcome therapy resistance in GBM.
{"title":"Metabolic profiling of glioblastoma stem cells reveals pyruvate carboxylase as a critical survival factor and potential therapeutic target.","authors":"Ophélie Renoult, Mélanie Laurent-Blond, Hala Awada, Lisa Oliver, Noémie Joalland, Mikaël Croyal, François Paris, Catherine Gratas, Claire Pecqueur","doi":"10.1093/neuonc/noae106","DOIUrl":"10.1093/neuonc/noae106","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) is a highly aggressive tumor with unmet therapeutic needs, which can be explained by extensive intra-tumoral heterogeneity and plasticity. In this study, we aimed to investigate the specific metabolic features of Glioblastoma stem cells (GSC), a rare tumor subpopulation involved in tumor growth and therapy resistance.</p><p><strong>Methods: </strong>We conducted comprehensive analyses of primary patient-derived GBM cultures and GSC-enriched cultures of human GBM cell lines using state-of-the-art molecular, metabolic, and phenotypic studies.</p><p><strong>Results: </strong>We showed that GSC-enriched cultures display distinct glycolytic profiles compared with differentiated tumor cells. Further analysis revealed that GSC relies on pyruvate carboxylase (PC) activity for survival and self-renewal capacity. Interestingly, inhibition of PC led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of PC restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models.</p><p><strong>Conclusions: </strong>Our findings demonstrate the critical role of PC in GSC metabolism, survival, and escape to etoposide. They also highlight PC as a therapeutic target to overcome therapy resistance in GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311287","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":"Corrigendum to: \"Ras-mediated modulation of pyruvate dehydrogenase activity regulates mitochondrial reserve capacity and contributes to glioblastoma tumorigenesis\".","authors":"","doi":"10.1093/neuonc/noae156","DOIUrl":"https://doi.org/10.1093/neuonc/noae156","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109999","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}
Liang Zeng, Ying-Qing Li, Shi-Wei He, Hui Xu, Ruizhong Zhang, Kai Chen, Liang-Jun Qin, Xun-Hua Zhu, Yi-Lin Li, Le Li, Na Liu, Hai-Yun Wang
Background: Dysregulated deubiquitinating enzymes (DUBs) execute as intrinsic oncogenes or tumor suppressors and are involved in chemoresistance in cancers. However, the functions and exact molecular mechanisms remain largely unclear in neuroblastoma.
Methods: Here, a R2 screening strategy based on the standard deviation values was used to identify the most important DUB, USP44, in neuroblastoma with stage 4. We validated the role of USP44 regulation upon cisplatin treatment in vitro and in vivo experiments, revealing the molecular mechanisms associated with USP44 regulation and cisplatin sensitivity in neuroblastoma.
Results: We found that low USP44 expression was associated with an inferior prognosis in neuroblastoma patients. Overexpression of USP44 enhanced neuroblastoma cell sensitivity to cisplatin in vitro and in vivo. Mechanistically, USP44 recruited and stabilized the E3 ubiquitin ligase STUB1 by removing its K48-linked polyubiquitin chains at Lys30, and STUB1 further reinforced the K48-linked polyubiquitination of LRPPRC at Lys453 and promoted its protein degradation, thus enhancing the accumulation of mitochondrial reactive oxygen species (mROS), in turn facilitating neuroblastoma cell apoptosis and cisplatin sensitivity. Additionally, overexpression of LRPPRC reversed the promoting effect of USP44 on cell apoptosis in cisplatin-treated neuroblastoma cells.
Conclusions: Our findings demonstrate that the USP44-STUB1-LRPPRC axis plays a pivotal role in neuroblastoma chemoresistance and provides potential targets for neuroblastoma therapy and prognostication.
{"title":"The deubiquitinase USP44 enhances cisplatin chemosensitivity through stabilizing STUB1 to promote LRPPRC degradation in neuroblastoma.","authors":"Liang Zeng, Ying-Qing Li, Shi-Wei He, Hui Xu, Ruizhong Zhang, Kai Chen, Liang-Jun Qin, Xun-Hua Zhu, Yi-Lin Li, Le Li, Na Liu, Hai-Yun Wang","doi":"10.1093/neuonc/noae175","DOIUrl":"https://doi.org/10.1093/neuonc/noae175","url":null,"abstract":"<p><strong>Background: </strong>Dysregulated deubiquitinating enzymes (DUBs) execute as intrinsic oncogenes or tumor suppressors and are involved in chemoresistance in cancers. However, the functions and exact molecular mechanisms remain largely unclear in neuroblastoma.</p><p><strong>Methods: </strong>Here, a R2 screening strategy based on the standard deviation values was used to identify the most important DUB, USP44, in neuroblastoma with stage 4. We validated the role of USP44 regulation upon cisplatin treatment in vitro and in vivo experiments, revealing the molecular mechanisms associated with USP44 regulation and cisplatin sensitivity in neuroblastoma.</p><p><strong>Results: </strong>We found that low USP44 expression was associated with an inferior prognosis in neuroblastoma patients. Overexpression of USP44 enhanced neuroblastoma cell sensitivity to cisplatin in vitro and in vivo. Mechanistically, USP44 recruited and stabilized the E3 ubiquitin ligase STUB1 by removing its K48-linked polyubiquitin chains at Lys30, and STUB1 further reinforced the K48-linked polyubiquitination of LRPPRC at Lys453 and promoted its protein degradation, thus enhancing the accumulation of mitochondrial reactive oxygen species (mROS), in turn facilitating neuroblastoma cell apoptosis and cisplatin sensitivity. Additionally, overexpression of LRPPRC reversed the promoting effect of USP44 on cell apoptosis in cisplatin-treated neuroblastoma cells.</p><p><strong>Conclusions: </strong>Our findings demonstrate that the USP44-STUB1-LRPPRC axis plays a pivotal role in neuroblastoma chemoresistance and provides potential targets for neuroblastoma therapy and prognostication.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110031","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}
Kim Hoa Ho, Marleen Trapp, Catello Guida, Ekaterina L Ivanova, Anchel De Jaime-Soguero, Ammar Jabali, Christian Thomas, Alena Salasova, Ondřej Bernatík, Chiara Salio, Sandra Horschitz, Martin Hasselblatt, Marco Sassoe-Pognetto, Lukáš Čajánek, Hiroshi Ishikawa, Horst Schroten, Christian Schwerk, Sergio P Acebrón, Peter Angel, Philipp Koch, Annarita Patrizi
Background: Choroid plexus (ChP) is the secretory epithelial structure located in brain ventricles. Choroid plexus tumors (CPTs) are rare neoplasms predominantly occurring in young patients with intensified malignancy in children. CPT treatment is hindered by insufficient knowledge of the tumor pathology and limited availability of valid models.
Methods: Genomic and transcriptomic data from CPT patients were analyzed to identify the putative pathological pathway. Cellular and molecular techniques were employed to validate bioinformatic results in CPT patient samples. Pharmacologic inhibition of Wnt/β-catenin signaling was assessed in CPT cells. Cell-based assays of ChP cell lines were performed following CRISPR-Cas9-derived knockout and over-expression of Wnt/β-catenin pathway genes. 3D CPT model was generated through CRISPR-Cas9-derived knockout of APC.
Results: We discovered that Wnt/β-catenin signaling is activated in human CPTs, likely as a consequence of large-scale chromosomal instability events of the CPT genomes. We demonstrated that CPT-derived cells depend on autocrine Wnt/β-catenin signaling for survival. Constitutive Wnt/β-catenin pathway activation, either through knock-out of the negative regulator APC or overexpression of the ligand WNT3A, induced tumorigenic properties in ChP 2D in vitro models. Increased activation of Wnt/β-catenin pathway in ChP organoids, through treatment with a potent GSK3β inhibitor, reduced the differentiation of mature ChP epithelia cells. Remarkably, the depletion of APC was sufficient to induce the oncogenic transformation of ChP organoids.
Conclusions: Our research identifies Wnt/β-catenin signaling as a critical driver of CPT tumorigenesis and provides the first 3D in vitro model for future pathological and therapeutic studies of CPT.
{"title":"Activation of Wnt/β-catenin signaling is critical for the tumorigenesis of choroid plexus.","authors":"Kim Hoa Ho, Marleen Trapp, Catello Guida, Ekaterina L Ivanova, Anchel De Jaime-Soguero, Ammar Jabali, Christian Thomas, Alena Salasova, Ondřej Bernatík, Chiara Salio, Sandra Horschitz, Martin Hasselblatt, Marco Sassoe-Pognetto, Lukáš Čajánek, Hiroshi Ishikawa, Horst Schroten, Christian Schwerk, Sergio P Acebrón, Peter Angel, Philipp Koch, Annarita Patrizi","doi":"10.1093/neuonc/noae176","DOIUrl":"https://doi.org/10.1093/neuonc/noae176","url":null,"abstract":"<p><strong>Background: </strong>Choroid plexus (ChP) is the secretory epithelial structure located in brain ventricles. Choroid plexus tumors (CPTs) are rare neoplasms predominantly occurring in young patients with intensified malignancy in children. CPT treatment is hindered by insufficient knowledge of the tumor pathology and limited availability of valid models.</p><p><strong>Methods: </strong>Genomic and transcriptomic data from CPT patients were analyzed to identify the putative pathological pathway. Cellular and molecular techniques were employed to validate bioinformatic results in CPT patient samples. Pharmacologic inhibition of Wnt/β-catenin signaling was assessed in CPT cells. Cell-based assays of ChP cell lines were performed following CRISPR-Cas9-derived knockout and over-expression of Wnt/β-catenin pathway genes. 3D CPT model was generated through CRISPR-Cas9-derived knockout of APC.</p><p><strong>Results: </strong>We discovered that Wnt/β-catenin signaling is activated in human CPTs, likely as a consequence of large-scale chromosomal instability events of the CPT genomes. We demonstrated that CPT-derived cells depend on autocrine Wnt/β-catenin signaling for survival. Constitutive Wnt/β-catenin pathway activation, either through knock-out of the negative regulator APC or overexpression of the ligand WNT3A, induced tumorigenic properties in ChP 2D in vitro models. Increased activation of Wnt/β-catenin pathway in ChP organoids, through treatment with a potent GSK3β inhibitor, reduced the differentiation of mature ChP epithelia cells. Remarkably, the depletion of APC was sufficient to induce the oncogenic transformation of ChP organoids.</p><p><strong>Conclusions: </strong>Our research identifies Wnt/β-catenin signaling as a critical driver of CPT tumorigenesis and provides the first 3D in vitro model for future pathological and therapeutic studies of CPT.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109986","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}
Alyssa M Pereslete, Melissa E Hughes, Alyssa R Martin, Janet Files, Kyleen Nguyen, Lauren Buckley, Ashka Patel, Abigail Moore, Eric P Winer, Deborah Dillon, Tianyu Li, Sara M Tolaney, Nancy U Lin, Sarah L Sammons
Background: There are limited data regarding HER2-low expression dynamics between matched primary tumors and brain metastases (BrMs) in breast cancer. HER2-low expression has emerged as a new therapeutic biomarker for highly active antibody-drug conjugates with emerging intracranial activity.
Methods: Patients with metastatic breast cancer (MBC) and BrMs seen at an NCI-designated center between 2003-2023 were identified. HER2 expression was defined as HER2-positive (3+,2+/ISH amplified), HER2-low (1+,2+/ISH negative), or HER2-0 by ASCO-CAP guidelines. Estrogen receptor (ER) status was defined as ER≥1%. Multivariate survival analyses by Cox proportional hazard models were determined from time of BrM resection to death or last follow-up between the 3 subtypes, controlling for ER and age.
Results: Among 197 matched primary and resected BrMs, 81% exhibited HER2 expression in the brain:61% HER2-positive, 20% HER2-low, and 19% HER2-0. Concordance was high in HER2-positive primary tumors with 100% retaining HER2 expression (97% retained HER2+ expression and 2.7% switched to HER2-low). HER2-0 primaries frequently showed HER2 gain in BrMs to HER2-low (35%) or HER2-positive (5.4%) status. Among 48 HER2-low primary tumors, 52% were discordant for HER2 status in the brain with 21% testing HER2-positive and 31% testing HER2-0. In adjusted analyses, patients with HER2-positive BrMs had significantly lower death risk than patients with HER2-low BrMs (HR=0.41, P=0.0006); no difference was observed between HER2-0 and HER2-low.
Conclusions: In this retrospective analysis, HER2 expression is common in breast cancer BrMs, emphasizing the need for improved, non-invasive diagnostics. Patients with HER2-low and HER2-0 BrMs face inferior survival, presenting an unmet clinical need.
{"title":"Analysis of HER2 expression changes from breast primary to brain metastases and the impact of HER2-low expression on overall survival.","authors":"Alyssa M Pereslete, Melissa E Hughes, Alyssa R Martin, Janet Files, Kyleen Nguyen, Lauren Buckley, Ashka Patel, Abigail Moore, Eric P Winer, Deborah Dillon, Tianyu Li, Sara M Tolaney, Nancy U Lin, Sarah L Sammons","doi":"10.1093/neuonc/noae163","DOIUrl":"https://doi.org/10.1093/neuonc/noae163","url":null,"abstract":"<p><strong>Background: </strong>There are limited data regarding HER2-low expression dynamics between matched primary tumors and brain metastases (BrMs) in breast cancer. HER2-low expression has emerged as a new therapeutic biomarker for highly active antibody-drug conjugates with emerging intracranial activity.</p><p><strong>Methods: </strong>Patients with metastatic breast cancer (MBC) and BrMs seen at an NCI-designated center between 2003-2023 were identified. HER2 expression was defined as HER2-positive (3+,2+/ISH amplified), HER2-low (1+,2+/ISH negative), or HER2-0 by ASCO-CAP guidelines. Estrogen receptor (ER) status was defined as ER≥1%. Multivariate survival analyses by Cox proportional hazard models were determined from time of BrM resection to death or last follow-up between the 3 subtypes, controlling for ER and age.</p><p><strong>Results: </strong>Among 197 matched primary and resected BrMs, 81% exhibited HER2 expression in the brain:61% HER2-positive, 20% HER2-low, and 19% HER2-0. Concordance was high in HER2-positive primary tumors with 100% retaining HER2 expression (97% retained HER2+ expression and 2.7% switched to HER2-low). HER2-0 primaries frequently showed HER2 gain in BrMs to HER2-low (35%) or HER2-positive (5.4%) status. Among 48 HER2-low primary tumors, 52% were discordant for HER2 status in the brain with 21% testing HER2-positive and 31% testing HER2-0. In adjusted analyses, patients with HER2-positive BrMs had significantly lower death risk than patients with HER2-low BrMs (HR=0.41, P=0.0006); no difference was observed between HER2-0 and HER2-low.</p><p><strong>Conclusions: </strong>In this retrospective analysis, HER2 expression is common in breast cancer BrMs, emphasizing the need for improved, non-invasive diagnostics. Patients with HER2-low and HER2-0 BrMs face inferior survival, presenting an unmet clinical need.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109997","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}