bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–12–24
fourteen papers selected by
Oltea Sampetrean, Keio University
  1. Immunological sex differences in glioblastoma.
  2. H3 K27M-altered Glioma and Diffuse Intrinsic Pontine Glioma: Semi-systematic Review of Treatment Landscape and Future Directions.
  3. High connectivity in gliomas affects cognition and survival.
  4. Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma.
  5. The duality of CXCR3 in glioblastoma: unveiling autocrine and paracrine mechanisms for novel therapeutic approaches.
  6. Single-cell characterization of human GBM reveals regional differences in tumor-infiltrating leukocyte activation.
  7. The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen.
  8. Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity.
  9. Diffuse midline glioma, H3K27-altered: Illuminating the dark side of the moon.
  10. An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.
  11. Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.
  12. Rational combination platform trial design for children and young adults with Diffuse Midline Glioma: a report from PNOC.
  13. Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma.
  14. Abrogation of the G2/M checkpoint as a chemo sensitization approach for alkylating agents.
  1. Nat Cancer. 2023 Dec;4(12): 1636
    Immunological sex differences in glioblastoma.
    Felicity Tournant.
      
    DOI:  https://doi.org/10.1038/s43018-023-00660-6
  2. Neuro Oncol. 2023 Dec 15. pii: noad220. [Epub ahead of print]
    H3 K27M-altered Glioma and Diffuse Intrinsic Pontine Glioma: Semi-systematic Review of Treatment Landscape and Future Directions.
    Martin van den Bent, Amanda M Saratsis, Marjolein Geurts, Enrico Franceschi.
      H3 K27M-mutant diffuse glioma is a recently identified brain tumor associated with poor prognosis. As of 2016, it is classified by the World Health Organization as a distinct form of grade IV glioma. Despite recognition as an important prognostic and diagnostic feature in diffuse glioma, radiation remains the sole standard of care and no effective systemic therapies are available for H3K27M mutant tumors. This review will detail treatment interventions applied to diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG) prior to the identification of the H3 K27M mutation, the current standard-of-care for H3 K27M-mutant diffuse glioma treatment, and ongoing clinical trials listed on w w w.clinicaltrials.gov evaluating novel therapeutics in this population. Current clinical trials were identified using clinicaltrials.gov, and studies qualifying for this analysis were active or ongoing interventional trials that evaluated a therapy in at least one treatment arm or cohort comprised exclusively of patients with DIPG and H3 K27M-mutant glioma. Forty-one studies met these criteria, including trials evaluating H3 K27M vaccination, chimeric antigen-receptor T cell therapy, and small molecule inhibitors. Ongoing evaluation of novel therapeutics is necessary to identify safe and effective interventions in this underserved patient population.
    Keywords:  H3 K27-altered; H3 K27M; clinical trials; diffuse intrinsic pontine glioma; diffuse midline glioma
    DOI:  https://doi.org/10.1093/neuonc/noad220
  3. Nat Cancer. 2023 Dec;4(12): 1637
    High connectivity in gliomas affects cognition and survival.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s43018-023-00661-5
  4. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad132
    Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma.
    Sabbir Khan, Emmanuel Martinez-Ledesma, Jianwen Dong, Rajasekaran Mahalingam, Soon Young Park, Yuji Piao, Dimpy Koul, Veerakumar Balasubramaniyan, John F de Groot, W K Alfred Yung.
       Background: Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%-50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment. We tested the therapeutic potential of MEK1/2 inhibitors in glioblastoma using 3D cultures of glioma stem-like cells (GSCs) and mouse models of glioblastoma.
    Methods: Several MEK inhibitors were screened in an unbiased high-throughput platform using GSCs. Cell death was evaluated using flow cytometry and Western blotting (WB) analysis. RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and WB analysis were used to identify and validate neuronal differentiation.
    Results: Unbiased screening of multiple MEK inhibitors in GSCs showed antiproliferative and apoptotic cell death in sensitive cell lines. An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4). We validated the neuronal differentiation phenotypes in vitro and in vivo using selected differentiation markers (β-III-tubulin, ASCL1, DLL3, and NeuroD4). Oral treatment with trametinib in an orthotopic GSC xenograft model significantly improved animal survival, with 25%-30% of mice being long-term survivors.
    Conclusions: Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling.
    Keywords:  EGFR-MEK signaling; MEK inhibitors; apoptosis; glioblastoma; neuronal differentiation
    DOI:  https://doi.org/10.1093/noajnl/vdad132
  5. Cell Death Dis. 2023 Dec 16. 14(12): 835
    The duality of CXCR3 in glioblastoma: unveiling autocrine and paracrine mechanisms for novel therapeutic approaches.
    Travis Yui Hei Chan, Jenny Sum Yee Wong, Karrie Mei-Yee Kiang, Cherry Won Yuet Sun, Gilberto Ka-Kit Leung.
      Glioblastoma (GBM) is a highly aggressive brain tumor associated with limited therapeutic options and a poor prognosis. CXCR3, a chemokine receptor, serves dual autocrine-paracrine functions in cancer. Despite gaps in our understanding of the functional role of the CXCR3 receptor in GBM, it has been shown to hold promise as a therapeutic target for the treatment of GBM. Existing clinical therapeutics and vaccines targeting CXCR3 ligand expression associated with the CXCR3 axes have also shown anti-tumorigenic effects in GBM. This review summarizes existing evidence on the oncogenic function of CXCR3 and its ligands CXCL9, CXCL10, and CXCL11, in GBM, and examines the controversies concerning the immunomodulatory functions of the CXCR3 receptor, including immune T cell recruitment, polarization, and positioning. The mechanisms underlying monotherpies and combination therapies targeting the CXCR3 pathways are discussed. A better understanding of the CXCR3 axes may lead to the development of strategies for overcoming the limitations of existing immunotherapies for GBM.
    DOI:  https://doi.org/10.1038/s41419-023-06354-2
  6. Elife. 2023 Dec 21. pii: RP92678. [Epub ahead of print]12
    Single-cell characterization of human GBM reveals regional differences in tumor-infiltrating leukocyte activation.
    Philip Schmassmann, Julien Roux, Steffen Dettling, Sabrina Hogan, Tala Shekarian, Tomás A Martins, Marie-Françoise Ritz, Sylvia Herter, Marina Bacac, Gregor Hutter.
      Glioblastoma (GBM) harbors a highly immunosuppressive tumor microenvironment (TME) which influences glioma growth. Major efforts have been undertaken to describe the TME on a single-cell level. However, human data on regional differences within the TME remain scarce. Here, we performed high-depth single-cell RNA sequencing (scRNAseq) on paired biopsies from the tumor center, peripheral infiltration zone and blood of five primary GBM patients. Through analysis of >45,000 cells, we revealed a regionally distinct transcription profile of microglia (MG) and monocyte-derived macrophages (MdMs) and an impaired activation signature in the tumor-peripheral cytotoxic-cell compartment. Comparing tumor-infiltrating CD8+ T cells with circulating cells identified CX3CR1high and CX3CR1int CD8+ T cells with effector and memory phenotype, respectively, enriched in blood but absent in the TME. Tumor CD8+ T cells displayed a tissue-resident memory phenotype with dysfunctional features. Our analysis provides a regionally resolved mapping of transcriptional states in GBM-associated leukocytes, serving as an additional asset in the effort towards novel therapeutic strategies to combat this fatal disease.
    Keywords:  cancer biology; glioblastoma; human; scRNAseq; tumor microenvironment
    DOI:  https://doi.org/10.7554/eLife.92678
  7. Cancer Res. 2023 Dec 20.
    The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen.
    Tathiane M Malta, Thais S Sabedot, Natalia S Morosini, Indrani Datta, Luciano Garofano, Wies R Vallentgoed, Frederick S Varn, Kenneth Aldape, Fulvio D'Angelo, Spyridon Bakas, Jill S Barnholtz-Sloan, Hui K Gan, Mohammad Hasanain, Ann-Christin Hau, Kevin C Johnson, Simona Cazacu, Ana C deCarvalho, Mustafa Khasraw, Emre Kocakavuk, Mathilde C M Kouwenhoven, Simona Migliozzi, Simone P Niclou, Johanna M Niers, D Ryan Ormond, Sun Ha Paek, Guido Reifenberger, Peter A Sillevis Smitt, Marion Smits, Lucy F Stead, Martin J van den Bent, Erwin G Van Meir, Annemiek Walenkamp, Tobias Weiss, Michael Weller, Bart A Westerman, Bauke Ylstra, Pieter Wesseling, Anna Lasorella, Pim J French, Laila M Poisson, The Glass Consortium, Roel G W Verhaak, Antonio Iavarone, Houtan Noushmehr.
      Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histological progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution towards an IDHwt-like phenotype.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2093
  8. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad152
    Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity.
    Maikel Verduin, Linde Hoosemans, Maxime Vanmechelen, Mike van Heumen, Jolanda A F Piepers, Galuh Astuti, Linda Ackermans, Olaf E M G Schijns, Kim R Kampen, Vivianne C G Tjan-Heijnen, Buys A de Barbanson, Alida A Postma, Danielle B P Eekers, Martijn P G Broen, Jan Beckervordersandforth, Katerina Staňková, Frederik de Smet, Jeremy Rich, Christopher G Hubert, Gregory Gimenez, Aniruddha Chatterjee, Ann Hoeben, Marc A Vooijs.
       Background: Treatment resistance and tumor relapse are the primary causes of mortality in glioblastoma (GBM), with intratumoral heterogeneity playing a significant role. Patient-derived cancer organoids have emerged as a promising model capable of recapitulating tumor heterogeneity. Our objective was to develop patient-derived GBM organoids (PGO) to investigate treatment response and resistance.
    Methods: GBM samples were used to generate PGOs and analyzed using whole-exome sequencing (WES) and single-cell karyotype sequencing. PGOs were subjected to temozolomide (TMZ) to assess viability. Bulk RNA sequencing was performed before and after TMZ.
    Results: WES analysis on individual PGOs cultured for 3 time points (1-3 months) showed a high inter-organoid correlation and retention of genetic variants (range 92.3%-97.7%). Most variants were retained in the PGO compared to the tumor (range 58%-90%) and exhibited similar copy number variations. Single-cell karyotype sequencing demonstrated preservation of genetic heterogeneity. Single-cell multiplex immunofluorescence showed maintenance of cellular states. TMZ treatment of PGOs showed a differential response, which largely corresponded with MGMT promoter methylation. Differentially expressed genes before and after TMZ revealed an upregulation of the JNK kinase pathway. Notably, the combination treatment of a JNK kinase inhibitor and TMZ demonstrated a synergistic effect.
    Conclusions: Overall, these findings demonstrate the robustness of PGOs in retaining the genetic and phenotypic heterogeneity in culture and the application of measuring clinically relevant drug responses. These data show that PGOs have the potential to be further developed into avatars for personalized adaptive treatment selection and actionable drug target discovery and as a platform to study GBM biology.
    Keywords:  glioblastoma; organoids; preclinical models; temozolomide resistance; tumor heterogeneity
    DOI:  https://doi.org/10.1093/noajnl/vdad152
  9. Neuro Oncol. 2023 Dec 18. pii: noad245. [Epub ahead of print]
    Diffuse midline glioma, H3K27-altered: Illuminating the dark side of the moon.
    Matthew D Dun, Yazmin Odia, Isabel Arrillaga-Romany.
      
    DOI:  https://doi.org/10.1093/neuonc/noad245
  10. Cell Rep. 2023 Dec 18. pii: S2211-1247(23)01569-3. [Epub ahead of print]43(1): 113557
    An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.
    Stephanie M Casillo, Taylor A Gatesman, Akanksha Chilukuri, Srinidhi Varadharajan, Brenden J Johnson, Daniel R David Premkumar, Esther P Jane, Tritan J Plute, Robert F Koncar, Ann-Catherine J Stanton, Carlos A O Biagi-Junior, Callie S Barber, Matthew E Halbert, Brian J Golbourn, Katharine Halligan, Andrea F Cruz, Neveen M Mansi, Allison Cheney, Steven J Mullett, Clinton Van't Land, Jennifer L Perez, Max I Myers, Nishant Agrawal, Joshua J Michel, Yue-Fang Chang, Olena M Vaske, Antony MichaelRaj, Frank S Lieberman, James Felker, Sruti Shiva, Kelsey C Bertrand, Nduka Amankulor, Costas G Hadjipanayis, Kalil G Abdullah, Pascal O Zinn, Robert M Friedlander, Taylor J Abel, Javad Nazarian, Sriram Venneti, Mariella G Filbin, Stacy L Gelhaus, Stephen C Mack, Ian F Pollack, Sameer Agnihotri.
      Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.
    Keywords:  CP: Cancer; CP: Metabolism; ERK5; H3K27a-DMG; MEF2A; PFKFB3; glioma; glycolysis; metabolism; multi targeted; pediatric; synergy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113557
  11. Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00445-X. [Epub ahead of print]
    Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.
    Aida Rashidi, Leah K Billingham, Andrew Zolp, Tzu-Yi Chia, Caylee Silvers, Joshua L Katz, Cheol H Park, Suzi Delay, Lauren Boland, Yuheng Geng, Steven M Markwell, Crismita Dmello, Victor A Arrieta, Kaylee Zilinger, Irene M Jacob, Aurora Lopez-Rosas, David Hou, Brandyn Castro, Alicia M Steffens, Kathleen McCortney, Jordain P Walshon, Mariah S Flowers, Hanchen Lin, Hanxiang Wang, Junfei Zhao, Adam Sonabend, Peng Zhang, Atique U Ahmed, Daniel J Brat, Dieter H Heiland, Catalina Lee-Chang, Maciej S Lesniak, Navdeep S Chandel, Jason Miska.
      Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.
    Keywords:  creatine metabolism; glioblastoma; myeloid cells; pseudopalisading necrosis
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.013
  12. Neuro Oncol. 2023 Dec 20. pii: noad181. [Epub ahead of print]
    Rational combination platform trial design for children and young adults with Diffuse Midline Glioma: a report from PNOC.
    Sabine Mueller, Cassie Kline, Andrea Franson, Jasper van der Lugt, Michael Prados, Sebastian M Waszak, Sabine Plasschaert, Annette M Molinaro, Carl Koschmann, Javad Nazarian.
      Diffuse midline glioma (DMG) is a devastating pediatric brain tumor unresponsive to hundreds of clinical trials. Approximately 80% of DMGs harbor H3K27M oncohistones, which reprogram the epigenome to increase the metabolic profile of the tumor cells. We have previously shown preclinical efficacy of targeting both oxidative phosphorylation and glycolysis through treatment with ONC201, which activates the mitochondrial protease ClpP, and paxalisib, which inhibits PI3K/mTOR, respectively. This combination treatment aimed at inducing metabolic distress led to the design of the first DMG-specific platform trial PNOC022 (NCT05009992). Here, we expand on the PNOC022 rationale and discuss various considerations, including liquid biome, microbiome, and genomic biomarkers, quality-of-life endpoints, and novel imaging modalities, such that we offer direction on future clinical trials in DMG.
    DOI:  https://doi.org/10.1093/neuonc/noad181
  13. Cell. 2023 Dec 13. pii: S0092-8674(23)01317-X. [Epub ahead of print]
    Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma.
    Daniel Kirschenbaum, Ken Xie, Florian Ingelfinger, Yonatan Katzenelenbogen, Kathleen Abadie, Thomas Look, Fadi Sheban, Truong San Phan, Baoguo Li, Pascale Zwicky, Ido Yofe, Eyal David, Kfir Mazuz, Jinchao Hou, Yun Chen, Hila Shaim, Mayra Shanley, Soeren Becker, Jiawen Qian, Marco Colonna, Florent Ginhoux, Katayoun Rezvani, Fabian J Theis, Nir Yosef, Tobias Weiss, Assaf Weiner, Ido Amit.
      Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma. Within 24 hours of tumor infiltration, cytotoxic natural killer cells transitioned to a dysfunctional program regulated by TGFB1 signaling. Infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by the upregulation of suppressive myeloid checkpoints Trem2, Il18bp, and Arg1, over 36 to 48 hours. Treatment with an antagonistic anti-TREM2 antibody reshaped the tumor microenvironment by redirecting the monocyte trajectory toward pro-inflammatory macrophages. Zman-seq is a broadly applicable technology, enabling empirical measurements of differentiation trajectories, which can enhance the development of more efficacious immunotherapies.
    Keywords:  cancer; computational biology; dynamics; glioblastoma; immunology; immunotherapy; single-cell biology; systems immunology; temporal transcriptomics; tumor-associated-macrophages
    DOI:  https://doi.org/10.1016/j.cell.2023.11.032
  14. Neuro Oncol. 2023 Dec 22. pii: noad252. [Epub ahead of print]
    Abrogation of the G2/M checkpoint as a chemo sensitization approach for alkylating agents.
    Fengchao Lang, James A Cornwell, Karambir Kaur, Omar Elmogazy, Wei Zhang, Meili Zhang, Hua Song, Zhonghe Sun, Xiaolin Wu, Mirit I Aladjem, Michael Aregger, Steven D Cappell, Chunzhang Yang.
       BACKGROUND: The cell cycle is tightly regulated by checkpoints, playing a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anti-cancer treatments, allowing for DNA repair prior to cell division. Manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies.
    METHODS: In this study, we conducted a forward genome wide CRISPR/Cas9 screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress.
    RESULTS: Our findings revealed that canonical DNA repair pathways, including ATM/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of PKMYT1, in ensuring cell survival. Depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between alkylating agents and a Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice.
    CONCLUSION: Collectively, our findings highlight the potential of targeting cell cycle timing through Myt1 inhibition as an effective strategy to enhance the efficacy of current standard cancer therapies, potentially leading to improved disease outcomes.
    Keywords:  Chemotherapy; Glioma; Myt1 kinase; alkylating agent; mitosis
    DOI:  https://doi.org/10.1093/neuonc/noad252
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