bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–10–29
fourteen papers selected by
Oltea Sampetrean, Keio University
  1. Refinement of diagnostic criteria for pediatric-type diffuse high-grade glioma, IDH- and H3-wildtype, MYCN-subtype including histopathology, TP53, MYCN and ID2 status.
  2. LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.
  3. Targeting network circuitry in glioma.
  4. Glioblastoma initiation, migration, and cell types are regulated by core bHLH transcription factors ASCL1 and OLIG2.
  5. The role of branched-chain aminotransferase 1 in driving glioblastoma cell proliferation and invasion varies with tumor subtype.
  6. `Frequencies of four Tumor-infiltrating lymphocytes potently predict survival in glioblastoma, an immune desert.
  7. IDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma.
  8. CD8+CD103+PD1+TIM3+ T cells in glioblastoma microenvironment correlate with prognosis.
  9. Proteometabolomics of initial and recurrent glioblastoma highlights an increased immune cell signature with altered lipid metabolism.
  10. Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma.
  11. Oxidative stress is involved in immunosuppression and macrophage regulation in glioblastoma.
  12. Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas.
  13. Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.
  14. Systematic Characterization of Antibody-Drug Conjugate Targets in Central Nervous System Tumors.
  1. Acta Neuropathol Commun. 2023 10 24. 11(1): 170
    Refinement of diagnostic criteria for pediatric-type diffuse high-grade glioma, IDH- and H3-wildtype, MYCN-subtype including histopathology, TP53, MYCN and ID2 status.
    Arnault Tauziède-Espariat, Emmanuelle Uro-Coste, Yvan Nicaise, Philipp Sievers, Andreas von Deimling, Felix Sahm, Oumaima Aboubakr, Alice Métais, Fabrice Chrétien, Pascale Varlet.
      
    DOI:  https://doi.org/10.1186/s40478-023-01667-x
  2. Res Sq. 2023 Oct 05. pii: rs.3.rs-3401154. [Epub ahead of print]
    LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.
    Peiwen Chen, Fatima Khan, Yiyu Lin, Heba Ali, Lizhi Pang, Madeline Dunterman, Wen-Hao Hsu, Katie Frenis, R Grant Rowe, Derek Wainwright, Kathleen McCortney, Leah Billingham, Jason Miska, Craig Horbinski, Maciej Lesniak.
      Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase (LDH) inhibitor stiripentol (an FDA-approved anti-seizure drug for Dravet Syndrome) emerges as the top hit. Combined profiling and functional studies demonstrate that LDHA-directed ERK pathway activates YAP1/STAT3 transcriptional co-activators in glioblastoma cells to upregulate CCL2 and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
    DOI:  https://doi.org/10.21203/rs.3.rs-3401154/v1
  3. Nat Cancer. 2023 Oct;4(10): 1406-1407
    Targeting network circuitry in glioma.
    Stephen M Robbins, Donna L Senger.
      
    DOI:  https://doi.org/10.1038/s43018-023-00640-w
  4. bioRxiv. 2023 Oct 02. pii: 2023.09.30.560206. [Epub ahead of print]
    Glioblastoma initiation, migration, and cell types are regulated by core bHLH transcription factors ASCL1 and OLIG2.
    Bianca L Myers, Kathryn J Brayer, Luis E Paez-Beltran, Matthew S Keith, Hideaki Suzuki, Jessie Newville, Rebekka H Anderson, Yunee Lo, Conner M Mertz, Rahul Kollipara, Mark D Borromeo, Robert M Bachoo, Jane E Johnson, Tou Yia Vue.
      Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex driver mutations and glioma stem cells (GSCs). The neurodevelopmental transcription factors ASCL1 and OLIG2 are co-expressed in GBMs, but their role in regulating the heterogeneity and hierarchy of GBM tumor cells is unclear. Here, we show that oncogenic driver mutations lead to dysregulation of ASCL1 and OLIG2, which function redundantly to initiate brain tumor formation in a mouse model of GBM. Subsequently, the dynamic levels and reciprocal binding of ASCL1 and OLIG2 to each other and to downstream target genes then determine the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in defining GSCs by upregulating a collection of ribosomal protein, mitochondrial, neural stem cell (NSC), and cancer metastasis genes - all essential for sustaining the high proliferation, migration, and therapeutic resistance of GSCs.
    DOI:  https://doi.org/10.1101/2023.09.30.560206
  5. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad120
    The role of branched-chain aminotransferase 1 in driving glioblastoma cell proliferation and invasion varies with tumor subtype.
    Maria Fala, Susana Ros, Ashley Sawle, Jyotsna U Rao, Anastasia Tsyben, Laura Tronci, Christian Frezza, Richard Mair, Kevin M Brindle.
       Background: Branched-chain aminotransferase 1 (BCAT1) has been proposed to drive proliferation and invasion of isocitrate dehydrogenase (IDH) wild-type glioblastoma cells. However, the Cancer Genome Atlas (TCGA) dataset shows considerable variation in the expression of this enzyme in glioblastoma. The aim of this study was to determine the role of BCAT1 in driving the proliferation and invasion of glioblastoma cells and xenografts that have widely differing levels of BCAT1 expression and the mechanism responsible.
    Methods: The activity of BCAT1 was modulated in IDH wild-type patient-derived glioblastoma cell lines, and in orthotopically implanted tumors derived from these cells, to examine the effects of BCAT1 expression on tumor phenotype.
    Results: In cells with constitutively high BCAT1 expression and a glycolytic metabolic phenotype, inducible shRNA knockdown of the enzyme resulted in reduced proliferation and invasion by increasing the concentration of α-ketoglutarate, leading to reduced DNA methylation, HIF-1α destabilization, and reduced expression of the transcription factor Forkhead box protein M1 (FOXM1). Conversely, overexpression of the enzyme increased HIF-1α expression and promoted proliferation and invasion. However, in cells with an oxidative phenotype and very low constitutive expression of BCAT1 increased expression of the enzyme had no effect on invasion and reduced cell proliferation. This occurred despite an increase in HIF-1α levels and could be explained by decreased TCA cycle flux.
    Conclusions: There is a wide variation in BCAT1 expression in glioblastoma and its role in proliferation and invasion is dependent on tumor subtype.
    Keywords:  alpha-ketoglutarate; branched-chain aminotransferase; glioblastoma; hypoxia-inducible factor; proliferation
    DOI:  https://doi.org/10.1093/noajnl/vdad120
  6. Neuro Oncol. 2023 Oct 23. pii: noad204. [Epub ahead of print]
    `Frequencies of four Tumor-infiltrating lymphocytes potently predict survival in glioblastoma, an immune desert.
    Rotem Gershon, Antonina Polevikov, Yevgeny Karepov, Anatoly Shenkar, Idan Ben-Horin, Tal Alter Regev, Meytal Dror-Levinsky, Kelly Lipczyc, Lital Gasri-Plotnitsky, Gil Diamant, Nati Shapira, Barak Bensimhon, Aharon Hagai, Tal Shahar, Rachel Grossman, Zvi Ram, Ilan Volovitz.
       BACKGROUND: GBM is an aggressive grade 4 primary brain tumor (BT), with a 5%-13% 5-year survival. Most human GBMs manifest as immunologically "cold" tumors, or "immune deserts", yet the promoting or suppressive roles of specific lymphocytes within the GBM tumor microenvironment (TME) is of considerable debate.
    PATIENTS AND METHODS: We used meticulous multiparametric flow cytometry (FC) to determine the lymphocytic frequencies in 102 GBMs, lower-grade gliomas, brain metastases, and non-tumorous brain specimen. FC-attained frequencies were compared with frequencies estimated by "digital cytometry". The FC-derived data were combined with the patients' demographic, clinical, molecular, histopathological, radiological, and survival data.
    RESULTS: Comparison of FC-derived data to CIBERSORT-estimated data revealed the poor capacity of digital cytometry to estimate cell frequencies below 0.2%, the frequency range of most immune cells in BTs. Isocitrate dehydrogenase (IDH) mutation status was found to affect TME composition more than the gliomas' pathological grade. Combining FC and survival data disclosed that unlike other cancer types, the frequency of helper T cells (Th) and cytotoxic T lymphocytes (CTL) correlated negatively with glioma survival. In contrast, the frequencies of γδ-T cells and CD56bright natural killer (NK) cells correlated positively with survival. A composite parameter combining the frequencies of these four tumoral lymphocytes separated the survival curves of GBM patients with a median difference of 10 months (FC-derived data; P<0.0001, discovery cohort), or 4.1 months (CIBERSORT-estimated data; P=0.01, validation cohort).
    CONCLUSION: The frequencies of four TME lymphocytes strongly correlate with the survival of patients with GBM, a tumor considered an immune desert.
    Keywords:  Cancer; Flow cytometry; Glioblastoma; Immunotherapy; digital cytometry
    DOI:  https://doi.org/10.1093/neuonc/noad204
  7. Nat Commun. 2023 Oct 25. 14(1): 6781
    IDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma.
    Xueqin Chen, Jun Liu, Yuqin Li, Yuequan Zeng, Fang Wang, Zexiong Cheng, Hao Duan, Guopeng Pan, Shangqi Yang, Yuling Chen, Qing Li, Xi Shen, Ying Li, Zixi Qin, Jiahong Chen, Youwei Huang, Xiangyu Wang, Yuli Lu, Minfeng Shu, Yubo Zhang, Guocai Wang, Kai Li, Xi Lin, Fan Xing, Haipeng Zhang.
      IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSVΔ51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy.
    DOI:  https://doi.org/10.1038/s41467-023-42545-3
  8. Immunology. 2023 Oct 26.
    CD8+CD103+PD1+TIM3+ T cells in glioblastoma microenvironment correlate with prognosis.
    Giulia Romagnoli, Quintino Giorgio D'Alessandris, Imerio Capone, Andrea Tavilla, Irene Canini, Caterina Lapenta, Mariachiara Buccarelli, Martina Giordano, Valentina Tirelli, Massimo Sanchez, Alessandra Fragale, Stefano Giannetti, Rina Di Bonaventura, Liverana Lauretti, Mauro Biffoni, Lucia Ricci-Vitiani, Roberto Pallini, Lucia Gabriele.
      Glioblastoma, isocitrate dehydrogenase-wildtype (GB), is the most common and aggressive primary brain malignancy with poor outcome. Immune checkpoint inhibitors (ICIs) have been tested in GB and, despite disappointing results, the identification of a small subgroup of responders underlies the need to improve our understanding of the tumour microenvironment (TME) immunity. This study aimed to determine whether the expression of selected immune checkpoints on tissue-resident memory T cells (Trm) may predict patient outcome. We conducted a single cohort observational study. Tumour samples were collected from 45 patients with histologically confirmed GB (WHO grade 4) and processed to obtain single-cell suspensions. Patients were assessed for the correlation of Trm phenotype with overall survival (OS) or progression-free survival (PFS) using multiparametric flow cytometry and uni/multivariate analyses. Levels of Trm expressing programmed cell death protein 1 (PD1) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) were found to be linked to clinical outcome. Low frequency of Trm expressing PD1 or TIM3 or both markers defined subgroups as independent positive prognostic factors for patient survival. On multivariate analysis, low CD8+CD103+PD1+TIM3+ Trm and Karnofsky performance status (KPS) ≥70 were confirmed to be the most predictive independent factors associated with longer OS (hazard ratios-HR [95%CI]: 0.14 [0.04-0.52] p < 0.001, 0.39 [0.16-0.96] p = 0.04, respectively). The CD8+CD103+ Trm subgroups were also age-related predictors for survival in GB.
    Keywords:  PD1; TIM3; age; disease outcome; glioblastoma; predictors; tissue-resident memory T cells (Trm)
    DOI:  https://doi.org/10.1111/imm.13710
  9. Neuro Oncol. 2023 Oct 26. pii: noad208. [Epub ahead of print]
    Proteometabolomics of initial and recurrent glioblastoma highlights an increased immune cell signature with altered lipid metabolism.
    Miguel Cosenza-Contreras, Agnes Schäfer, Justin Sing, Lena Cook, Maren N Stillger, Chia-Yi Chen, Jose Villacorta Hidalgo, Niko Pinter, Larissa Meyer, Tilman Werner, Darleen Bug, Zeno Haberl, Oliver Kübeck, Kai Zhao, Susanne Stei, Anca Violeta Gafencu, Radu Ionita, Felix M Brehar, Jaime Ferrer-Lozano, Gloria Ribas, Leo Cerdá-Alberich, Luis Martí-Bonmatí, Christopher Nimsky, Alexis Van Straaten, Martin L Biniossek, Melanie Föll, Nina Cabezas-Wallscheid, Jörg Büscher, Hannes Röst, Armelle Arnoux, Jörg W Bartsch, Oliver Schilling.
       BACKGROUND: There is an urgent need to better understand the mechanisms associated with the development, progression, and onset of recurrence after initial surgery in glioblastoma (GBM). The use of integrative phenotype-focused -omics technologies such as proteomics and lipidomics provides an unbiased approach to explore the molecular evolution of the tumor and its associated environment.
    METHODS: We assembled a cohort of patient-matched initial (iGBM) and recurrent (rGBM) specimens of resected GBM. Proteome and metabolome composition were determined by mass spectrometry-based techniques. We performed neutrophil-GBM cell co-culture experiments to evaluate the behavior of rGBM-enriched proteins in the tumor microenvironment. ELISA-based quantitation of candidate proteins was performed to test the association of their plasma concentrations in iGBM with the onset of recurrence.
    RESULTS: Proteomic profiles reflect increased immune cell infiltration and extracellular matrix reorganization in rGBM. ASAH1, SYMN, and GPNMB were highly enriched proteins in rGBM. Lipidomics indicates the downregulation of ceramides in rGBM. Cell analyses suggest a role for ASAH1 in neutrophils and its localization in extracellular traps. Plasma concentrations of ASAH1 and SYNM show an association with time-to-recurrence.
    CONCLUSIONS: We describe the potential importance of ASAH1 in tumor progression and development of rGBM via metabolic rearrangement and showcase the feedback from the tumor microenvironment to plasma proteome profiles. We report the potential of ASAH1 and SYNM as plasma markers of rGBM progression. The published datasets can be considered as a resource for further functional and biomarker studies involving additional -omics technologies.
    Keywords:  acid ceramidase (ASAH1); glioblastoma; lipidomics; proteomics; tumor microenvironment
    DOI:  https://doi.org/10.1093/neuonc/noad208
  10. Sci Adv. 2023 Oct 27. 9(43): eadf1332
    Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma.
    Brett W Stringer, Manam Inushi De Silva, Zarina Greenberg, Alejandra Noreña Puerta, Robert Adams, Bridget Milky, Michael Zabolocki, Mark van den Hurk, Lisa M Ebert, Christine Fairly Bishop, Simon J Conn, Ganessan Kichenadasse, Michael Z Michael, Rebecca J Ormsby, Santosh Poonoose, Cedric Bardy.
      Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
    DOI:  https://doi.org/10.1126/sciadv.adf1332
  11. Clin Immunol. 2023 Oct 20. pii: S1521-6616(23)00565-X. [Epub ahead of print] 109802
    Oxidative stress is involved in immunosuppression and macrophage regulation in glioblastoma.
    Xisong Liang, Zeyu Wang, Ziyu Dai, Jian Liu, Hao Zhang, Jie Wen, Nan Zhang, Jian Zhang, Peng Luo, Zaoqu Liu, Zhixiong Liu, Quan Cheng.
      Oxidative stress dually affected cancer progression, while its effect on glioblastomas remained unclear. Herein, we clustered the multicenter glioblastoma cohorts based on the oxidative-stress-responsive genes (OSS) expression. We found that cluster 2 with high OSS levels suffered a worse prognosis. Functional analyses and immune-related analyses results exhibited that M2-like pro-tumoral macrophages and neutrophils were enriched in cluster 2, while Natural killer cells' infiltration was decreased. The increased M2-like pro-tumoral macrophages in cluster 2 was confirmed by immunofluorescence. An integrated single-cell analysis validated the malignant features of cluster 2 neoplastic cells and discovered their crosstalk with M2-like pro-tumoral macrophages. Moreover, we observed that SOD3 knockdown increased the M1-like anti-tumoral transformation and decreased the M2-like pro-tumoral transformation of macrophage in vitro and in vivo. Comprehensively, we revealed oxidative stress' prognostic and immunosuppressive potential in glioblastoma and confirmed SOD3's role in regulating macrophage M2-like pro-tumoral transformation, providing novel targets for developing TME-targeted strategies.
    Keywords:  Glioblastoma; Macrophage; Microglia; Oxidative stress; SOD3
    DOI:  https://doi.org/10.1016/j.clim.2023.109802
  12. Sci Rep. 2023 Oct 27. 13(1): 18436
    Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas.
    Gábor Bedics, Péter Szőke, Bence Bátai, Tibor Nagy, Gergő Papp, Noémi Kránitz, Hajnalka Rajnai, Lilla Reiniger, Csaba Bödör, Bálint Scheich.
      Glioblastomas are the most common IDH-wildtype adult high-grade gliomas, frequently harboring mutations in the TERT gene promoter (pTERT) and utilizing the subsequent telomerase overexpression for telomere length maintenance. However, some rare cases show loss of ATRX and use alternative mechanisms of telomere lengthening. In this study, we performed the first complex genomic analysis specifically concentrating on the latter subgroup. Comprehensive genomic profiling of 12 ATRX-deficient and 13 ATRX-intact IDH-wildtype adult high-grade gliomas revealed that ATRX and pTERT mutations are mutually exclusive. DNMT3A alterations were confined to ATRX-deficient, while PTEN mutations to ATRX-intact cases. RAS-MAPK pathway alterations, including NF1 mutations, were more characteristic in the ATRX-deficient group. Variants of genes related to homologous recombination repair showed different patterns of affected genes. Two ATRX-deficient tumors with high tumor mutational burden and mismatch repair deficiency were found. One of these contained a novel fusion involving the NTRK2 and LRRFIP2 genes, while the other showed loss of MSH2 and MSH6 without genetic alterations in the encoding genes suggesting an epigenetic background. Genetic characteristics of ATRX-deficient IDH-wildtype adult high-grade gliomas suggest that these tumors are particularly intriguing targets of potential future therapeutic interventions including immunotherapies combined with MAPK pathway inhibition and DNA repair inhibitors.
    DOI:  https://doi.org/10.1038/s41598-023-45786-w
  13. Sci Adv. 2023 Oct 27. 9(43): eadi8986
    Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.
    Laura M Bartos, Sabrina V Kirchleitner, Zeynep Ilgin Kolabas, Stefanie Quach, Alexander Beck, Julia Lorenz, Jens Blobner, Stephan A Mueller, Selin Ulukaya, Luciano Hoeher, Izabela Horvath, Karin Wind-Mark, Adrien Holzgreve, Viktoria C Ruf, Lukas Gold, Lea H Kunze, Sebastian T Kunte, Philipp Beumers, Ha Eun Park, Melissa Antons, Artem Zatcepin, Nils Briel, Leonie Hoermann, Rebecca Schaefer, Denise Messerer, Peter Bartenstein, Markus J Riemenschneider, Simon Lindner, Sibylle Ziegler, Jochen Herms, Stefan F Lichtenthaler, Ali Ertürk, Joerg C Tonn, Louisa von Baumgarten, Nathalie L Albert, Matthias Brendel.
      Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma; however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands.
    DOI:  https://doi.org/10.1126/sciadv.adi8986
  14. Neuro Oncol. 2023 Oct 23. pii: noad205. [Epub ahead of print]
    Systematic Characterization of Antibody-Drug Conjugate Targets in Central Nervous System Tumors.
    Shannon Coy, Jong Suk Lee, Sabrina J Chan, Terri Woo, Jacquelyn Jones, Sanda Alexandrescu, Patrick Y Wen, Peter K Sorger, Keith L Ligon, Sandro Santagata.
       BACKGROUND: Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid and hematologic malignancies, including those expressing HER2, TROP2, and NECTIN4. Recently, an ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level expression of ADC targets may be sufficient for treatment responsiveness. However, ADC target expression is poorly characterized in many central nervous system (CNS) tumors.
    METHODS: We analyzed publicly available RNA-sequencing and proteomic data from the Children's Brain Tumor Network (N=188 tumors) and gene-expression-omnibus (GEO) RNA-expression datasets (N=356) to evaluate expression of 14 potential ADC targets that are FDA-approved or under investigation in solid cancers. We also used immunohistochemistry to measure the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma, oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (N=575).
    RESULTS: Pan-CNS analysis showed subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas strongly expressed HER2, while meningiomas showed weak-moderate HER2 expression. ACP and PCP strongly expressed B7-H3, with TROP2 expression in whorled ACP epithelium. AT/RT strongly expressed CLDN6. Glioblastoma showed little subtype-specific marker expression, suggesting a need for further target development.
    CONCLUSIONS: CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be warranted.
    Keywords:  Craniopharyngioma; Ependymoma; Glioma; Immunoconjugates; Meningioma
    DOI:  https://doi.org/10.1093/neuonc/noad205
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