bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024‒06‒16
ten papers selected by
Oltea Sampetrean, Keio University
  1. Glioblastoma and brain connectivity: the need for a paradigm shift.
  2. Tumor growth in recurrent glioblastoma-RANO: when to plan the baseline scan?
  3. Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network.
  4. Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma.
  5. NRG-BN002: Phase I Study of Ipilimumab, Nivolumab, and the Combination in Patients with Newly Diagnosed GBM.
  6. Mapping myeloid cell function: Spatial diversity in tumor and neuronal microenvironment.
  7. Protocol for qualitative analysis of lysosome immunoprecipitation from patient-derived glioblastoma stem-like cells.
  8. Editorial: Spatiotemporal heterogeneity in CNS tumors.
  9. Targeting IGF2-IGF1R Signaling to Reprogram the Tumor Microenvironment for Enhanced Viro-Immunotherapy.
  10. Leveraging murine models of the neurofibromatosis type 1 cancer predisposition syndrome to elucidate the cellular circuits that drive pediatric low-grade glioma formation and progression.
  1. Lancet Neurol. 2024 Jul;pii: S1474-4422(24)00160-1. [Epub ahead of print]23(7): 740-748
    Glioblastoma and brain connectivity: the need for a paradigm shift.
    Alessandro Salvalaggio, Lorenzo Pini, Alessandra Bertoldo, Maurizio Corbetta.
      Despite substantial advances in cancer treatment, for patients with glioblastoma prognosis remains bleak. The emerging field of cancer neuroscience reveals intricate functional interplays between glioblastoma and the cellular architecture of the brain, encompassing neurons, glia, and vessels. New findings underscore the role of structural and functional connections within hierarchical networks, known as the connectome. These connections contribute to the location, spread, and recurrence of a glioblastoma, and a patient's overall survival, revealing a complex interplay between the tumour and the CNS. This mounting evidence prompts a paradigm shift, challenging the perception of glioblastomas as mere foreign bodies within the brain. Instead, these tumours are intricately woven into the structural and functional fabric of the brain. This radical change in thinking holds profound implications for the understanding and treatment of glioblastomas, which could unveil new prognostic factors and surgical strategies and optimise radiotherapy. Additionally, a connectivity approach suggests that non-invasive brain stimulation could disrupt pathological neuron-glioma interactions within specific networks.
    DOI:  https://doi.org/10.1016/S1474-4422(24)00160-1
  2. Neuro Oncol. 2024 Jun 10. pii: noae095. [Epub ahead of print]
    Tumor growth in recurrent glioblastoma-RANO: when to plan the baseline scan?
    Lisa Dobber, Marjolein Geurts, Martin J van den Bent.
      
    DOI:  https://doi.org/10.1093/neuonc/noae095
  3. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae078
    Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network.
    POLA Network
      Background: Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population.Methods: Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%.
    Results: Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects.
    Conclusions: Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.
    Keywords:  IDH; clinical trial; high-grade gliomas; olaparib
    DOI:  https://doi.org/10.1093/noajnl/vdae078
  4. Nat Cell Biol. 2024 Jun;26(6): 1003-1018
    Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma.
    Lele Wu, Zheng Zhao, Yong Jae Shin, Yiyun Yin, Anandhkumar Raju, Thamil Selvan Vaiyapuri, Khaireen Idzham, Miseol Son, Yeri Lee, Jason K Sa, Joelle Yi Heng Chua, Bilal Unal, You Zhai, Wenhua Fan, Lijie Huang, Huimin Hu, Jayantha Gunaratne, Do-Hyun Nam, Tao Jiang, Vinay Tergaonkar.
      Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.
    DOI:  https://doi.org/10.1038/s41556-024-01428-5
  5. Neuro Oncol. 2024 Jun 14. pii: noae058. [Epub ahead of print]
    NRG-BN002: Phase I Study of Ipilimumab, Nivolumab, and the Combination in Patients with Newly Diagnosed GBM.
    Andrew E Sloan, Kathryn Winter, Mark R Gilbert, Kenneth Aldape, Serah Choi, Patrick Y Wen, Nicholas Butowski, Fabio M Iwamoto, Raju R Raval, Alfredo D Voloschin, Carlos Kamiya-Matsuoka, Minhee Won, Minesh P Mehta.
      BACKGROUND: Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting.METHODS: The primary endpoint was dose limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results.
    RESULTS: Thirty-two patients were enrolled at 9 institutions; 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% white. Treatment was well tolerated with a 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. Median follow-up was 19.6 mo. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 mo. and 16.1 mo., respectively.
    CONCLUSIONS: IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant TMZ for newly diagnosed GBM. Combination IPI+NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in a phase II/III for patients with newly diagnosed GBM.
    Keywords:  GBM; Immune checkpoint Inhibitor; Ipilimumab; Nivolumab; Phase I
    DOI:  https://doi.org/10.1093/neuonc/noae058
  6. Cancer Cell. 2024 Jun 10. pii: S1535-6108(24)00186-7. [Epub ahead of print]42(6): 934-936
    Mapping myeloid cell function: Spatial diversity in tumor and neuronal microenvironment.
    Giulia Villa, Daniel Delev, Dieter Henrik Heiland.
      In this issue of Cancer Cell, Zhong et al. explore the dual role of TREM2 in glioblastoma-associated myeloid cells, demonstrating its function in promoting inflammation at the tumor-neural interface and suppression within the tumor core, influenced by the local microenvironment. These findings open up promising prospects for advancements in neuro-oncological immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2024.05.018
  7. STAR Protoc. 2024 Jun 07. pii: S2666-1667(24)00286-7. [Epub ahead of print]5(2): 103121
    Protocol for qualitative analysis of lysosome immunoprecipitation from patient-derived glioblastoma stem-like cells.
    Clément Maghe, Julie Gavard.
      Lysosomes are critical for the sustenance of glioblastoma stem-like cells (GSCs) properties. We present a protocol to enrich and purify lysosomes from patient-derived GSCs in culture. We describe the steps required to stably express a tagged lysosomal protein in GSCs, mechanically lyse cells, magnetically immunopurify lysosomes, and qualitatively assess these organelles. We then detail the procedure for retrieving intact and purified lysosomes from GSCs. We also specify cell culture conditions, storage procedures, and sample preparation for immunoblotting. For complete details on the use and execution of this protocol, please refer to Maghe et al.1.
    Keywords:  Cancer; Cell Biology; Cell culture; Cell separation/fractionation; Molecular/Chemical Probes; Protein Biochemistry; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2024.103121
  8. Front Immunol. 2024 ;15 1430227
    Editorial: Spatiotemporal heterogeneity in CNS tumors.
    Syed M Faisal, Vidhya M Ravi, Jason M Miska.
      
    Keywords:  glioblastoma; multiplex spatial 3D mapping; single cell spatial analysis; spatial transcriptomics; spatiotemporal heterogeneity
    DOI:  https://doi.org/10.3389/fimmu.2024.1430227
  9. Neuro Oncol. 2024 Jun 10. pii: noae105. [Epub ahead of print]
    Targeting IGF2-IGF1R Signaling to Reprogram the Tumor Microenvironment for Enhanced Viro-Immunotherapy.
    Min Hye Noh, Jin Muk Kang, Alexandra A Miller, Grace Nguyen, Minxin Huang, Ji Seon Shim, Alberto J Bueso-Perez, Sara A Murphy, Kimberly A Rivera-Caraballo, Yoshihiro Otani, Eunju Kim, Seung-Hee Yoo, Yuanqing Yan, Yeshavanth Banasavadi-Siddegowda, Hiroshi Nakashima, E Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo.
      BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.
    RESULTS: Transcriptome analysis identified IGF2 as one of the top secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%) (p=0.0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8+cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice.
    CONCLUSION: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.
    Keywords:  Glioblastoma (GBM); Insulin-like growth factor 2 (IGF2); Insulin-like growth factor-1 receptor (IGF1R); Oncolytic herpes simplex virus-1 (oHSV); Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1093/neuonc/noae105
  10. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae054
    Leveraging murine models of the neurofibromatosis type 1 cancer predisposition syndrome to elucidate the cellular circuits that drive pediatric low-grade glioma formation and progression.
    David H Gutmann.
      Brain tumors are the leading cause of cancer-related death in children, where low-grade gliomas (LGGs) predominate. One common hereditary cause for LGGs involves neurofibromatosis-1 (NF1) gene mutation, as seen in individuals with the NF1 cancer predisposition syndrome. As such, children with NF1 are at increased risk of developing LGGs of the optic pathway, brainstem, cerebellum, and midline brain structures. Using genetically engineered mouse models, studies have revealed both cell-intrinsic (MEK signaling) and stromal dependencies that underlie their formation and growth. Importantly, these dependencies represent vulnerabilities against which targeted agents can be used for preclinical investigation prior to clinical translation.
    Keywords:  NF1; ecosystem; low-grade glioma; neurofibromatosis; optic glioma
    DOI:  https://doi.org/10.1093/noajnl/vdae054
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