bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–07–21
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. 3D Brain Vascular Niche Model Captures Invasive Behavior and Gene Signatures of Glioblastoma.
  2. Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme.
  3. Unraveling glioblastoma diversity: Insights into methylation subtypes and spatial relationships.
  4. Biomarkers of immunotherapy in glioblastoma.
  5. Accelerated tumor progression after COVID-19 infection in patients with glioblastoma: A retrospective case-control study.
  6. Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated BBB opening: A novel combinatorial immunotherapy regimen for gliomas.
  7. Hemizygous deletion of cyclin-dependent kinase inhibitor 2A/B with p16 immuno-negative and methylthioadenosine phosphorylase retention predicts poor prognosis in IDH-mutant adult glioma.
  8. NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma.
  9. Inhibition of PERK mediated UPR acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma.
  10. Pathways to hypermutation in high-grade gliomas: Mechanisms, syndromes, and opportunities for immunotherapy.
  11. Gut microbiota's role in glioblastoma risk, with a focus on the mediating role of metabolites.
  12. NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors.
  13. Maternal obesogenic diet operates at the tumor cell of origin to increase incidence and decrease latency of Neurofibromatosis Type 1 optic pathway glioma.
  1. bioRxiv. 2024 Jul 13. pii: 2024.07.09.601756. [Epub ahead of print]
    3D Brain Vascular Niche Model Captures Invasive Behavior and Gene Signatures of Glioblastoma.
    Vivian K Lee, Rut Tejero, Nathaniel Silvia, Anirudh Sattiraju, Aarthi Ramakrishnan, Li Shen, Alexandre Wojcinski, Santosh Kesari, Roland H Friedel, Hongyan Zou, Guohao Dai.
      Glioblastoma (GBM) is a lethal brain cancer with no effective treatment; understanding how GBM cells respond to tumor microenvironment remains challenging as conventional cell cultures lack proper cytoarchitecture while in vivo animal models present complexity all at once. Developing a culture system to bridge the gap is thus crucial. Here, we employed a multicellular approach using human glia and vascular cells to optimize a 3-dimensional (3D) brain vascular niche model that enabled not only long-term culture of patient derived GBM cells but also recapitulation of key features of GBM heterogeneity, in particular invasion behavior and vascular association. Comparative transcriptomics of identical patient derived GBM cells in 3D and in vivo xenotransplants models revealed that glia-vascular contact induced genes concerning neural/glia development, synaptic regulation, as well as immune suppression. This gene signature displayed region specific enrichment in the leading edge and microvascular proliferation zones in human GBM and predicted poor prognosis. Gene variance analysis also uncovered histone demethylation and xylosyltransferase activity as main themes for gene adaption of GBM cells in vivo . Furthermore, our 3D model also demonstrated the capacity to provide a quiescence and a protective niche against chemotherapy. In summary, an advanced 3D brain vascular model can bridge the gap between 2D cultures and in vivo models in capturing key features of GBM heterogeneity and unveil previously unrecognized influence of glia-vascular contact for transcriptional adaption in GBM cells featuring neural/synaptic interaction and immunosuppression.
    DOI:  https://doi.org/10.1101/2024.07.09.601756
  2. Cell Death Dis. 2024 Jul 13. 15(7): 503
    Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme.
    Jolie Bou-Gharios, Georges Noël, Hélène Burckel.
      Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard clinical treatment of GBM includes a maximal surgical resection followed by concomitant radiotherapy (RT) and chemotherapy sessions with Temozolomide (TMZ) in addition to adjuvant TMZ cycles. Despite the severity of this protocol, GBM is highly resistant and recurs in almost all cases while the protocol remains unchanged since 2005. Limited-diffusion or chronic hypoxia has been identified as one of the major key players driving this aggressive phenotype. The presence of hypoxia within the tumor bulk contributes to the activation of hypoxia signaling pathway mediated by the hypoxia-inducing factors (HIFs), which in turn activate biological mechanisms to ensure the adaptation and survival of GBM under limited oxygen and nutrient supply. Activated downstream pathways are involved in maintaining stem cell-like phenotype, inducing mesenchymal shift, invasion, and migration, altering the cellular and oxygen metabolism, and increasing angiogenesis, autophagy, and immunosuppression. Therefore, in this review will discuss the recent preclinical and clinical approaches that aim at targeting tumor hypoxia to enhance the response of GBM to conventional therapies along with their results and limitations upon clinical translation.
    DOI:  https://doi.org/10.1038/s41419-024-06904-2
  3. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae112
    Unraveling glioblastoma diversity: Insights into methylation subtypes and spatial relationships.
    Martha Foltyn-Dumitru, Haidar Alzaid, Aditya Rastogi, Ulf Neuberger, Felix Sahm, Tobias Kessler, Wolfgang Wick, Martin Bendszus, Philipp Vollmuth, Marianne Schell.
       Background: The purpose of this study was to elucidate the relationship between distinct brain regions and molecular subtypes in glioblastoma (GB), focusing on integrating modern statistical tools and molecular profiling to better understand the heterogeneity of Isocitrate Dehydrogenase wild-type (IDH-wt) gliomas.
    Methods: This retrospective study comprised 441 patients diagnosed with new IDH-wt glioma between 2009 and 2020 at Heidelberg University Hospital. The diagnostic process included preoperative magnetic resonance imaging and molecular characterization, encompassing IDH-status determination and subclassification, through DNA-methylation profiling. To discern and map distinct brain regions associated with specific methylation subtypes, a support-vector regression-based lesion-symptom mapping (SVR-LSM) was employed. Lesion maps were adjusted to 2 mm³ resolution. Significance was assessed with beta maps, using a threshold of P < .005, with 10 000 permutations and a cluster size minimum of 100 voxels.
    Results: Of 441 initially screened glioma patients, 423 (95.9%) met the inclusion criteria. Following DNA-methylation profiling, patients were classified into RTK II (40.7%), MES (33.8%), RTK I (18%), and other methylation subclasses (7.6%). Between molecular subtypes, there was no difference in tumor volume. Using SVR-LSM, distinct brain regions correlated with each subclass were identified: MES subtypes were associated with left-hemispheric regions involving the superior temporal gyrus and insula cortex, RTK I with right frontal regions, and RTK II with 3 clusters in the left hemisphere.
    Conclusions: This study linked molecular diversity and spatial features in glioblastomas using SVR-LSM. Future studies should validate these findings in larger, independent cohorts to confirm the observed patterns.
    Keywords:  DNA methylation subtypes; MRI; glioblastoma; support vector regression-based lesion-symptom mapping
    DOI:  https://doi.org/10.1093/noajnl/vdae112
  4. Neurooncol Pract. 2024 Aug;11(4): 383-394
    Biomarkers of immunotherapy in glioblastoma.
    William M Savage, Mitchell D Yeary, Anthony J Tang, Colin P Sperring, Michael G Argenziano, Arjun R Adapa, Nina Yoh, Peter Canoll, Jeffrey N Bruce.
      Glioblastoma (GBM) is the most common primary brain cancer, comprising half of all malignant brain tumors. Patients with GBM have a poor prognosis, with a median survival of 14-15 months. Current therapies for GBM, including chemotherapy, radiotherapy, and surgical resection, remain inadequate. Novel therapies are required to extend patient survival. Although immunotherapy has shown promise in other cancers, including melanoma and non-small lung cancer, its efficacy in GBM has been limited to subsets of patients. Identifying biomarkers of immunotherapy response in GBM could help stratify patients, identify new therapeutic targets, and develop more effective treatments. This article reviews existing and emerging biomarkers of clinical response to immunotherapy in GBM. The scope of this review includes immune checkpoint inhibitor and antitumoral vaccination approaches, summarizing the variety of molecular, cellular, and computational methodologies that have been explored in the setting of anti-GBM immunotherapies.
    Keywords:  biomarkers; cancer immunotherapy; cancer vaccine; glioblastoma; immune checkpoint inhibitor
    DOI:  https://doi.org/10.1093/nop/npae028
  5. Neurooncol Pract. 2024 Aug;11(4): 475-483
    Accelerated tumor progression after COVID-19 infection in patients with glioblastoma: A retrospective case-control study.
    Timothy A Gregory, Stephanie R Knight, Ashley E Aaroe, Kaitlin N Highsmith, Zachary C Janatpour, Barbara J O'Brien, Nazanin K Majd, Monica E Loghin, Chirag B Patel, Shiao-Pei Weathers, Vinay K Puduvalli, Carlos Kamiya-Matsuoka.
       Background: We observed rapid tumor progression following COVID-19 infection among patients with glioblastoma and sought to systematically characterize their disease course in a retrospective case-control study.
    Methods: Using an institutional database, we retrospectively identified a series of COVID-19-positive glioblastoma cases and matched them by age and sex 1:2 to glioblastoma controls who had a negative COVID-19 test during their disease course. Demographic and clinical data were analyzed. Hyperprogression was defined using modified response evaluation criteria in solid tumors criteria. Time to progression and overall survival were estimated using the Kaplan-Meier method.
    Results: Thirty-two glioblastoma cases with positive COVID-19 testing were matched to 64 glioblastoma controls with negative testing; age, sex, and molecular profiles did not differ between groups. Progression events occurred in 27 cases (84%) and 46 controls (72%). Of these, 14 cases (52%) presented with multifocal disease or leptomeningeal disease at progression compared with 10 controls (22%; P = .0082). Hyperprogression was identified in 13 cases (48%) but only 4 controls (9%; P = .0001). Cases had disease progression at a median of 35 days following COVID-19 testing, compared with 164 days for controls (P = .0001). Median survival from COVID-19 testing until death was 8.3 months for cases but 17 months for controls (P = .0016). Median overall survival from glioblastoma diagnosis was 20.7 months for cases and 24.6 months for controls (P = .672).
    Conclusions: Patients with glioblastoma may have accelerated disease progression in the first 2 months after COVID-19 infection. Infected patients should be monitored vigilantly. Future investigations should explore tumor-immune microenvironment changes linking tumor progression and COVID-19.
    Keywords:  COVID-19; SARS-CoV-2; glioblastoma; glioma; progression
    DOI:  https://doi.org/10.1093/nop/npae029
  6. Neuro Oncol. 2024 Jul 19. pii: noae135. [Epub ahead of print]
    Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated BBB opening: A novel combinatorial immunotherapy regimen for gliomas.
    Kwang-Soo Kim, Karl Habashy, Andrew Gould, Junfei Zhao, Hinda Najem, Christina Amidei, Ruth Saganty, Víctor A Arrieta, Crismita Dmello, Li Chen, Daniel Y Zhang, Brandyn Castro, Leah Billingham, Daniel Levey, Olivia Huber, Marilyn Marques, David A Savitsky, Benjamin M Morin, Miguel Muzzio, Michael Canney, Craig Horbinski, Peng Zhang, Jason Miska, Surya Padney, Bin Zhang, Raul Rabadan, Joanna J Phillips, Nicholas Butowski, Amy B Heimberger, Jian Hu, Roger Stupp, Dhan Chand, Catalina Lee-Chang, Adam M Sonabend.
       BACKGROUND: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers.
    METHOD: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor associated macrophages/microglia (TAMs).
    RESULTS: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4 mediated selective depletion of intra-tumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge.
    CONCLUSION: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).
    Keywords:  BBB; Fc-enhanced anti-CTLA-4; Glioblastoma; doxorubicin; immunotherapy
    DOI:  https://doi.org/10.1093/neuonc/noae135
  7. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae069
    Hemizygous deletion of cyclin-dependent kinase inhibitor 2A/B with p16 immuno-negative and methylthioadenosine phosphorylase retention predicts poor prognosis in IDH-mutant adult glioma.
    Ryosuke Otsuji, Nobuhiro Hata, Hidetaka Yamamoto, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Naoki Noguchi, Aki Sako, Osamu Togao, Tadamasa Yoshitake, Akira Nakamizo, Masahiro Mizoguchi, Koji Yoshimoto.
       Background: Homozygous deletion of the tumor suppression genes cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH-mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH-mutant and 1p/19q-codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH-mutant gliomas.
    Methods: We enrolled 101 adults with IDH-mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA). Immunohistochemical analysis of p16/MTAP and promoter methylation analysis with methylation-specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan - Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression-free survival.
    Results: Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16-negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS: 38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (P = .0191) and 2.44 (P = .0943) for homozygous and hemizygous deletions, respectively.
    Conclusions: CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.
    Keywords:  CDKN2A/B; IDH-mutant glioma; MTAP; hemizygous deletion; p16
    DOI:  https://doi.org/10.1093/noajnl/vdae069
  8. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae095
    NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma.
    Radu O Minea, Thu Zan Thein, Zhuoyue Yang, Mihaela Campan, Pamela M Ward, Axel H Schönthal, Thomas C Chen.
       Background: The chemotherapeutic standard of care for patients with glioblastoma (GB) is radiation therapy (RT) combined with temozolomide (TMZ). However, during the twenty years since its introduction, this so-called Stupp protocol has revealed major drawbacks, because nearly half of all GBs harbor intrinsic treatment resistance mechanisms. Prime among these are the increased expression of the DNA repair protein O6-guanine-DNA methyltransferase (MGMT) and cellular deficiency in DNA mismatch repair (MMR). Patients with such tumors receive very little, if any, benefit from TMZ. We are developing a novel molecule, NEO212 (TMZ conjugated to NEO100), that harbors the potential to overcome these limitations.
    Methods: We used mouse models that were orthotopically implanted with GB cell lines or primary, radioresistant human GB stem cells, representing different treatment resistance mechanisms. Animals received NEO212 (or TMZ for comparison) without or with RT. Overall survival was recorded, and histology studies quantified DNA damage, apoptosis, microvessel density, and impact on bone marrow.
    Results: In all tumor models, replacing TMZ with NEO212 in a schedule designed to mimic the Stupp protocol achieved a strikingly superior extension of survival, especially in TMZ-resistant and RT-resistant models. While NEO212 displayed pronounced radiation-sensitizing, DNA-damaging, pro-apoptotic, and anti-angiogenic effects in tumor tissue, it did not cause bone marrow toxicity.
    Conclusions: NEO212 is a candidate drug to potentially replace TMZ within the standard Stupp protocol. It has the potential to become the first chemotherapeutic agent to significantly extend overall survival in TMZ-resistant patients when combined with radiation.
    Keywords:  O6-guanine-DNA methyltransferase; chemoradiation; mismatch repair deficiency; radiosensitization; temozolomide
    DOI:  https://doi.org/10.1093/noajnl/vdae095
  9. Neuro Oncol. 2024 Jul 18. pii: noae134. [Epub ahead of print]
    Inhibition of PERK mediated UPR acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma.
    Madhura Ketkar, Sanket Desai, Pranav Rana, Rahul Thorat, Sridhar Epari, Amit Dutt, Shilpee Dutt.
       BACKGROUND: Glioblastoma due to recurrence is clinically challenging with 10-15months overall survival. Previously we showed therapy induced senescence (TIS) in glioblastoma reverses causing recurrence. Here, we aim to delineate TIS reversal mechanism for potential therapeutic intervention to prevent GBM recurrence.
    METHODS: Residual senescent (RS) and End of Residual Senescence (ERS) cells were captured from GBM patient-derived primary-cultures and cell lines mimicking clinical scenario. RNA-sequencing, transcript/protein validations, knock-down/inhibitor studies, ChIP RT-PCR, biochemical assays and IHCs were performed for mechanistics of TIS reversal. In vivo validations were conducted in GBM orthotopic mouse model.
    RESULTS: Transcriptome analysis showed co-expression of ER stress-UPR and senescence associated secretory phenotype (SASP) with TIS induction and reversal. Robust SASP production and secretion by RS cells could induce senescence, ROS, DNA damage and ER stress in paracrine fashion independent of radiation. Neutralization of most significantly enriched cytokine from RS-secretome IL1β, suppressed SASP and delayed senescence reversal. Mechanistically, with SASP and massive protein accumulation in Endoplasmic reticulum, RS cells displayed stressed ER morphology, upregulated ER stress markers and PERK pathway activation via peIF2α-ATF4-CHOP which was spontaneously resolved in ERS. ChIP RT-PCR showed CHOP occupancy at CXCL8/IL8, CDKN1A/p21 and BCL2L1/BCLXL aiding survival. PERK knockdown/inhibition with GSK2606414 in combination with radiation led to sustained ER stress and senescence without SASP. PERKi in RS functioned as senolytic via apoptosis and prevented recurrence in vitro and in vivo ameliorating overall survival.
    CONCLUSION: We demonstrate that PERK mediated UPR regulates senescence reversal and its inhibition can be exploited as potential seno-therapeutic option in glioblastoma.
    Keywords:  ER stress; Glioblastoma; PERK; TIS reversal; Unfolded protein response
    DOI:  https://doi.org/10.1093/neuonc/noae134
  10. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae105
    Pathways to hypermutation in high-grade gliomas: Mechanisms, syndromes, and opportunities for immunotherapy.
    Tuesday Haynes, Mark R Gilbert, Kevin Breen, Chunzhang Yang.
      Despite rapid advances in the field of immunotherapy, including the success of immune checkpoint inhibition in treating multiple cancer types, clinical response in high-grade gliomas (HGGs) has been disappointing. This has been in part attributed to the low tumor mutational burden (TMB) of the majority of HGGs. Hypermutation is a recently characterized glioma signature that occurs in a small subset of cases, which may open an avenue to immunotherapy. The substantially elevated TMB of these tumors most commonly results from alterations in the DNA mismatch repair pathway in the setting of extensive exposure to temozolomide or, less frequently, from inherited cancer predisposition syndromes. In this review, we discuss the genetics and etiology of hypermutation in HGGs, with an emphasis on the resulting genomic signatures, and the state and future directions of immuno-oncology research in these patient populations.
    Keywords:  DNA mismatch repair; glioma; hypermutation; immune checkpoint inhibitor (ICI); temozolomide
    DOI:  https://doi.org/10.1093/noajnl/vdae105
  11. Front Neurol. 2024 ;15 1386885
    Gut microbiota's role in glioblastoma risk, with a focus on the mediating role of metabolites.
    Junqing Yan, Bo Li, Chun Luo.
      This study employed Mendelian randomization (MR) analysis to systematically investigate the potential connections between gut microbiota and the risk of glioblastoma (GBM). We identified 12 microbial groups closely associated with the incidence risk of GBM. Subsequently, MR analysis was conducted on 1,091 blood metabolites and 309 metabolite ratios, revealing 19 metabolites that exert an impact on the occurrence of GBM. Hypothesizing that gut microbiota may influence the risk of glioblastoma multiforme by modulating these metabolites, we performed MR analyses, considering each microbial group as exposure and each metabolite as an outcome. Through these analyses, we constructed a regulatory network encompassing gut microbiota, metabolites, and GBM, providing a novel perspective for a deeper understanding of the role of the gut-brain axis in the pathogenesis of GBM. This research offers crucial insights into how gut microbiota may affect the risk of GBM by regulating specific metabolites. The identified regulatory network of the gut-brain axis may play a significant role in the formation and development of GBM, providing valuable information for future research and therapeutic interventions.
    Keywords:  Mendelian randomization; brain-gut axis; glioblastoma; gut microbiota; metabolites
    DOI:  https://doi.org/10.3389/fneur.2024.1386885
  12. Acta Neuropathol Commun. 2024 Jul 16. 12(1): 118
    NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors.
    Eric Eunshik Kim, Chul-Kee Park, Seung-Ki Kim, Ji Hoon Phi, Sun Ha Paek, Jung Yoon Choi, Hyoung Jin Kang, Joo Ho Lee, Jae Kyung Won, Hongseok Yun, Sung-Hye Park.
      Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.
    Keywords:   NTRK fusion; Brain tumours; Next-generation sequencing; TRK inhibitors
    DOI:  https://doi.org/10.1186/s40478-024-01798-9
  13. Neuro Oncol. 2024 Jul 18. pii: noae136. [Epub ahead of print]
    Maternal obesogenic diet operates at the tumor cell of origin to increase incidence and decrease latency of Neurofibromatosis Type 1 optic pathway glioma.
    Ambrose Chan, Kailong Zhang, Gemma Martin, Sabiha Bano, Jit Chatterjee, Sarvika Mahto, Avery Wang, David H Gutmann, Nicole M Brossier.
       BACKGROUND: Pediatric low-grade glioma incidence has been rising in the U.S., mirroring the rising rates of pediatric and maternal obesity. Recently, children of obese mothers were demonstrated to develop brain tumors at higher rates. Importantly, obesity in the U.S. is largely driven by diet, given the prevalence of high fat and high sugar (HFHS) food choices. Since high-fat diet exposure can increase embryonic neuroglial progenitor cell (NPC) proliferation, the potential cells of origin for low-grade glioma, we hypothesized that in utero exposure to an obesogenic diet would modify pediatric brain penetrance and latency by affecting the tumor cell of origin.
    METHODS: We employed several murine models of the Neurofibromatosis type 1 (NF1) pediatric brain tumor predisposition syndrome, in which optic pathway gliomas (Nf1-OPGs) arise from NPCs in the embryonic third ventricular zone (TVZ). We exposed dams and offspring to an obesogenic HFHS diet or control chow and analysed fetal neurodevelopment at E19.5 and tumor formation at 6w-3mo.
    RESULTS: Progeny from HFHS diet-exposed dams demonstrated increased TVZ NPC proliferation and glial differentiation. Dietary switch cohorts confirmed that these effects were dependent upon maternal diet, rather than maternal weight. Obesogenic diet (Ob) similarly accelerated glioma formation in a high-penetrance Nf1-OPG strain and increased glioma penetrance in two low-penetrance Nf1-OPG strains. In contrast, Ob exposure in the postnatal period alone did not recapitulate these effects.
    CONCLUSIONS: These findings establish maternal obesogenic diet as a risk factor for murine Nf1-OPG formation, acting in part through in utero effects on the tumor cell of origin.
    Keywords:  maternal high-fat diet; neurofibromatosis; obesity; optic pathway glioma; pediatric brain tumor
    DOI:  https://doi.org/10.1093/neuonc/noae136
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