bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022‒10‒23
ten papers selected by
Oltea Sampetrean
Keio University
  1. Targeted nano-delivery of chemotherapy via intranasal route suppresses in vivo glioblastoma growth and prolongs survival in the intracranial mouse model.
  2. Blood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma.
  3. ATF4-dependent fructolysis fuels growth of glioblastoma multiforme.
  4. P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells.
  5. Transcriptomic and connectomic correlates of differential spatial patterning among gliomas.
  6. Glioblastoma stem cell-specific histamine secretion drives pro-angiogenic tumor microenvironment remodeling.
  7. A novel compound EPIC-0412 reverses temozolomide resistance via inhibiting DNA repair/MGMT in glioblastoma.
  8. Chronic convection-enhanced intratumoural delivery of chemotherapy for glioblastoma.
  9. Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.
  10. Intraventricular B7-H3 CAR T cells for diffuse intrinsic pontine glioma: preliminary first-in-human bioactivity and safety.
  1. Drug Deliv Transl Res. 2022 Oct 16.
    Targeted nano-delivery of chemotherapy via intranasal route suppresses in vivo glioblastoma growth and prolongs survival in the intracranial mouse model.
    Puja Sandbhor, Jayant Goda, Bhabani Mohanty, Poonam Gera, Sandhya Yadav, Godanjali Chekuri, Pradip Chaudhari, Shilpee Dutt, Rinti Banerjee.
      Nanotechnology-based drug delivery platforms have shown great potential in overcoming the limitations of conventional therapy for glioblastoma (GBM). However, permeation across the blood-brain barrier (BBB), physiological complexity of the brain, and glioma targeting strategies cannot entirely meet the challenging requirements of distinctive therapeutic delivery stages. The objective of this research is to fabricate lipid nanoparticles (LNPs) for the co-delivery of paclitaxel (PTX) and miltefosine (HePc) a proapoptotic agent decorated with transferrin (Tf-PTX-LNPs) and investigate its anti-glioma activity both in vitro and in vivo orthotopic NOD/SCID GBM mouse model. The present study demonstrates the anti-glioma effect of the dual drug combination of PTX and proapoptotic HePc lipid-based transferrin receptor (TfR) targeted alternative delivery (direct nose to brain transportation) of the nanoparticulate system (Tf-PTX-LNPs, 364 ± 5 nm, -43 ± 9 mV) to overcome the O6-methylguanine-DNA methyltransferase induce drug-resistant for improving the effectiveness of GBM therapy. The resulting nasally targeted LNPs present good biocompatibility, stability, high BBB transcytosis through selective TfR-mediated uptake by tumor cells, and effective tumor penetration in the brain of GBM induced mice. We observed markedly enhanced anti-proliferative efficacy of the targeted LNPs in U87MG cells compared to free drug. Nasal targeted LNPs had shown significantly improved brain concentration (Cmax fivefold and AUC0-24 4.9 fold) with early tmax (0.5 h) than the free drug. In vivo intracranial GBM-bearing targeted LNPs treated mice exhibited significantly prolonged survival with improved anti-tumor efficacy accompanied by reduced toxicity compared to systemic Taxol® and nasal free drug. These findings indicate that the nasal delivery of targeted synergistic nanocarrier holds great promise as a non-invasive adjuvant chemotherapy therapy of GBM.
    Keywords:  Blood–brain-barrier; Glioblastoma; Intracranial; Nanoparticles; Nasal delivery; Paclitaxel; Proapoptotic miltefosine
    DOI:  https://doi.org/10.1007/s13346-022-01220-8
  2. Nat Commun. 2022 Oct 20. 13(1): 6211
    Blood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma.
    Hyun-Jin Kim, Jang Hyun Park, Hyeon Cheol Kim, Chae Won Kim, In Kang, Heung Kyu Lee.
      Infiltrating tumor-associated macrophages (TAM) are known to impede immunotherapy against glioblastoma (GBM), however, TAMs are heterogeneous, and there are no clear markers to distinguish immunosuppressive and potentially immune-activating populations. Here we identify a subset of CD169+ macrophages promoting an anti-tumoral microenvironment in GBM. Using single-cell transcriptome analysis, we find that CD169+ macrophages in human and mouse gliomas produce pro-inflammatory chemokines, leading to the accumulation of T cells and NK cells. CD169 expression on macrophages facilitates phagocytosis of apoptotic glioma cells and hence tumor-specific T cell responses. Depletion of CD169+ macrophages leads to functionally impaired antitumor lymphocytes and poorer survival of glioma-bearing mice. We show that NK-cell-derived IFN-γ is critical for the accumulation of blood monocyte-derived CD169+ macrophages in gliomas. Our work thus identifies a well-distinguished TAM subset promoting antitumor immunity against GBM, and identifies key factors that might shift the balance from immunosuppressive to anti-tumor TAM.
    DOI:  https://doi.org/10.1038/s41467-022-34001-5
  3. Nat Commun. 2022 Oct 16. 13(1): 6108
    ATF4-dependent fructolysis fuels growth of glioblastoma multiforme.
    Chao Chen, Zhenxing Zhang, Caiyun Liu, Bin Wang, Ping Liu, Shu Fang, Fan Yang, Yongping You, Xinjian Li.
      Excessive consumption of fructose in the Western diet contributes to cancer development. However, it is still unclear how cancer cells coordinate glucose and fructose metabolism during tumor malignant progression. We demonstrate here that glioblastoma multiforme (GBM) cells switch their energy supply from glycolysis to fructolysis in response to glucose deprivation. Mechanistically, glucose deprivation induces expression of two essential fructolytic proteins GLUT5 and ALDOB through selectively activating translation of activating transcription factor 4 (ATF4). Functionally, genetic or pharmacological disruption of ATF4-dependent fructolysis significantly inhibits growth and colony formation of GBM cells in vitro and GBM growth in vivo. In addition, ATF4, GLUT5, and ALDOB levels positively correlate with each other in GBM specimens and are poor prognostic indicators in GBM patients. This work highlights ATF4-dependent fructolysis as a metabolic feature and a potential therapeutic target for GBM.
    DOI:  https://doi.org/10.1038/s41467-022-33859-9
  4. Nat Commun. 2022 Oct 19. 13(1): 6202
    P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells.
    Sree Deepthi Muthukrishnan, Riki Kawaguchi, Pooja Nair, Rachna Prasad, Yue Qin, Maverick Johnson, Qing Wang, Nathan VanderVeer-Harris, Amy Pham, Alvaro G Alvarado, Michael C Condro, Fuying Gao, Raymond Gau, Maria G Castro, Pedro R Lowenstein, Arjun Deb, Jason D Hinman, Frank Pajonk, Terry C Burns, Steven A Goldman, Daniel H Geschwind, Harley I Kornblum.
      Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.
    DOI:  https://doi.org/10.1038/s41467-022-33943-0
  5. Brain. 2022 Oct 18. pii: awac378. [Epub ahead of print]
    Transcriptomic and connectomic correlates of differential spatial patterning among gliomas.
    Rafael Romero-Garcia, Ayan S Mandal, Richard A I Bethlehem, Benedicto Crespo-Facorro, Michael G Hart, John Suckling.
      Unravelling the complex events driving grade-specific spatial distribution of brain tumour occurrence requires rich datasets from both healthy individuals and patients. Here, we combined open-access data from The Cancer Genome Atlas, the UKBiobank and the Allen Brain Human Atlas to disentangle how the different spatial occurrences of Glioblastoma Multiforme (GBM) and Low-Grade Gliomas (LGG) are linked to brain network features and the normative transcriptional profiles of brain regions. From MRI of brain tumour patients we first constructed a grade-related frequency map of the regional occurrence of LGG and the more aggressive GBM. Using associated mRNA transcription data, we derived a set of differential gene expressions from GBM and LGG tissues of the same patients. By combining the resulting values with normative gene expressions from postmortem brain tissue, we constructed a grade-related expression map indicating which brain regions express genes dysregulated in aggressive gliomas. Additionally, we derived an expression map of genes previously associated with tumour subtypes in a GWAS study (tumour-related genes). There were significant associations between grade-related frequency, grade-related expression, and tumour-related expression maps, as well as functional brain network features (specifically, nodal strength and participation coefficient) that are implicated in neurological and psychiatric disorders. These findings identify brain network dynamics and transcriptomic signatures as key factors in regional vulnerability for GBM and LGG occurrence, placing primary brain tumours within a well-established framework of neurological and psychiatric cortical alterations.
    Keywords:  connectomic; gene expression; glioma; transcriptomic
    DOI:  https://doi.org/10.1093/brain/awac378
  6. Cell Stem Cell. 2022 Oct 12. pii: S1934-5909(22)00417-9. [Epub ahead of print]
    Glioblastoma stem cell-specific histamine secretion drives pro-angiogenic tumor microenvironment remodeling.
    Jiayi Chen, Guangqin Liu, Xinzheng Wang, Hao Hong, Tingting Li, Lin Li, Hongxiang Wang, Jiong Xie, Bohan Li, Ting Li, Dingyi Lu, Yakun Zhang, Haixin Zhao, Chengcheng Yao, Kaiqing Wen, Teng Li, Jing Chen, Shengming Wu, Kun He, Wei-Na Zhang, Jie Zhao, Na Wang, Qiuying Han, Qing Xia, Ji Qi, Juxiang Chen, Tao Zhou, Jianghong Man, Xue-Min Zhang, Ai-Ling Li, Xin Pan.
      The communication between glioblastoma stem cells (GSCs) and the surrounding microenvironment is a prominent feature accounting for the aggressive biology of glioblastoma multiforme (GBM). However, the mechanisms by which GSCs proactively drive interactions with microenvironment is not well understood. In this study, we interrogated metabolites that are preferentially secreted from GSCs and found that GSCs produce and secrete histamine to shape a pro-angiogenic tumor microenvironment. This histamine-producing ability is attributed to H3K4me3 modification-activated histidine decarboxylase (HDC) transcription via MYC. Notably, HDC is highly expressed in GBM, which is associated with poor survival of these patients. GSC-secreted histamine activates endothelial cells by triggering a histamine H1 receptor (H1R)-Ca2+-NF-κB axis, thereby promoting angiogenesis and GBM progression. Importantly, pharmacological blockage of H1R using antihistamines impedes the growth of GBM xenografts in mice. Our findings establish that GSC-specific metabolite secretion remodels the tumor microenvironment and highlight histamine targeting as a potential strategy for GBM therapy.
    Keywords:  GBM; angiogenesis; epigenetics; glioblastoma stem cells; histamine; histidine decarboxylase; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.stem.2022.09.009
  7. Neuro Oncol. 2022 Oct 22. pii: noac242. [Epub ahead of print]
    A novel compound EPIC-0412 reverses temozolomide resistance via inhibiting DNA repair/MGMT in glioblastoma.
    Jixing Zhao, Shixue Yang, Xiaoteng Cui, Qixue Wang, Eryan Yang, Fei Tong, Biao Hong, Menglin Xiao, Lei Xin, Can Xu, Yanli Tan, Chunsheng Kang.
      BACKGROUND: TMZ resistance has become an important obstacle affecting its therapeutic benefits. O6-methylguanine DNA methyltransferase (MGMT) is primarily responsible for the TMZ resistance in GBM patients. Additionally, active DNA damage repair pathways can also lead to TMZ resistance. Here, we reported a novel small-molecule inhibitor EPIC-0412 that improved the therapeutic efficacy of TMZ by inhibiting the DNA damage repair pathway and MGMT in GBM via epigenetic pathways.METHODS: The small-molecule compound EPIC-0412 was obtained through high-throughput screening. RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), and chromatin immunoprecipitation (ChIP) assays were used to verify the effect of EPIC-0412. Co-immunoprecipitation (Co-IP) was used to elucidate the interactions of transcription factors at the MGMT promoter region. Animal experiments using a mouse model were performed to verify the efficacy of EPIC-0412 in sensitizing GBM cells to TMZ.
    RESULTS: EPIC-0412 physically interrupts the binding of HOTAIR and EZH2, leading to the upregulation of CDKN1A and BBC3, causing cell cycle arrest and apoptosis in GBM cells. EPIC-0412 inhibits DNA damage response in GBM cells through the p21-E2F1 DNA damage repair axis. EPIC-0412 epigenetically silences MGMT through its interaction with the ATF3-p-p65-HADC1 axis at the MGMT promoter region. The application of EPIC-0412 restored the TMZ sensitivity in GBM in vivo experiments.
    CONCLUSION: This study discovered a small-molecule inhibitor EPIC-0412, which enhanced the chemotherapeutic effect of TMZ by acting on the p21-E2F1 DNA damage repair axis and ATF3-p-p65-MGMT axis, providing evidence for combining epigenetic drugs to increase the sensitization toward TMZ in GBM patients.
    Keywords:  DNA repair; MGMT; glioblastoma; small-molecule inhibitor; temozolomide
    DOI:  https://doi.org/10.1093/neuonc/noac242
  8. Lancet Oncol. 2022 Oct 12. pii: S1470-2045(22)00626-X. [Epub ahead of print]
    Chronic convection-enhanced intratumoural delivery of chemotherapy for glioblastoma.
    Jacob S Young, Manish K Aghi.
      
    DOI:  https://doi.org/10.1016/S1470-2045(22)00626-X
  9. Acta Neuropathol. 2022 Oct 22.
    Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.
    Patrick J Cimino, Courtney Ketchum, Rust Turakulov, Omkar Singh, Zied Abdullaev, Caterina Giannini, Peter Pytel, Giselle Yvette Lopez, Howard Colman, MacLean P Nasrallah, Mariarita Santi, Igor Lima Fernandes, Jeff Nirschl, Sonika Dahiya, Stewart Neill, David Solomon, Eilis Perez, David Capper, Haresh Mani, Dario Caccamo, Matthew Ball, Michael Badruddoja, Rati Chkheidze, Sandra Camelo-Piragua, Joseph Fullmer, Sanda Alexandrescu, Gabrielle Yeaney, Charles Eberhart, Maria Martinez-Lage, Jie Chen, Leor Zach, B K Kleinschmidt-DeMasters, Marco Hefti, Maria-Beatriz Lopes, Nicholas Nuechterlein, Craig Horbinski, Fausto J Rodriguez, Martha Quezado, Drew Pratt, Kenneth Aldape.
      High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.
    Keywords:  DNA Methylation; HGAP; High-grade astrocytoma with piloid features; NF1; Neurofibromatosis type 1
    DOI:  https://doi.org/10.1007/s00401-022-02513-5
  10. Cancer Discov. 2022 Oct 19. pii: CD-22-0750. [Epub ahead of print]
    Intraventricular B7-H3 CAR T cells for diffuse intrinsic pontine glioma: preliminary first-in-human bioactivity and safety.
    Nicholas A Vitanza, Ashley L Wilson, Wenjun Huang, Kristy Seidel, Christopher Brown, Joshua A Gustafson, Jason K Yokoyama, Adam J Johnson, Blake A Baxter, Ryan W Koning, Aquene N Reid, Michael Meechan, Matthew C Biery, Carrie Myers, Stephanie D Rawlings-Rhea, Catherine M Albert, Samuel R Browd, Jason S Hauptman, Amy Lee, Jeffrey G Ojemann, Michael E Berens, Matthew D Dun, Jessica B Foster, Erin E Crotty, Sarah E S Leary, Bonnie L Cole, Francisco A Perez, Jason N Wright, Rimas J Orentas, Tony Chour, Evan W Newell, Jeffrey R Whiteaker, Lei Zhao, Amanda G Paulovich, Navin Pinto, Juliane Gust, Rebecca A Gardner, Michael C Jensen, Julie R Park.
      Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3-specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase 1 trial employing repeated locoregional B7-H3CARs to children with recurrent/refractory CNS tumors and DIPG. Here, we report results of the first 3 evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3CARs. Targeted mass spectrometry of CSF biospecimens revealed modulation in B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3CAR dosing, and that intracranial delivery may induce local immune activation.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0750
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