bims-malgli 2023-09-03 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2023–09–03
thirteen papers selected by
Oltea Sampetrean, Keio University

Metabolic partitioning in the brain and its hijacking by glioblastoma.
In vivo C6 glioma models: an update and a guide toward a more effective preclinical evaluation of potential anti-glioblastoma drugs.
Epidemiology and survival of adult-type diffuse glioma in Belgium during the molecular era.
MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value.
TREM2 promotes glioma progression and angiogenesis mediated by microglia/brain macrophages.
Spectral flow cytometry identifies distinct nonneoplastic plasma extracellular vesicle phenotype in glioblastoma patients.
Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial.
Altered plasma metabolite levels can be detected years before a glioma diagnosis.
Myeloid-specific KDM6B inhibition sensitizes glioblastoma to PD1 blockade.
EPIC-1042 as a potent PTRF/Cavin1-Caveolin-1 interaction inhibitor to induce PARP1 autophagic degradation and suppress temozolomide efflux for Glioblastoma.
Combined gene therapies for high-grade glioma.
Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain tumors.
Phase II Trial of Dabrafenib Plus Trametinib in Relapsed/Refractory BRAF V600-Mutant Pediatric High-Grade Glioma.

Genes Dev. 2023 Aug 30.

Metabolic partitioning in the brain and its hijacking by glioblastoma.

Jed de Ruiter Swain, Evdokia Michalopoulou, Evan K Noch, Michael J Lukey, Linda Van Aelst.

  The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.

Keywords:  IDH mutation; brain metabolism; cancer metabolism; glioblastoma; glioma; glioma therapy; immune suppression; tumor microenvironment

DOI:  https://doi.org/10.1101/gad.350693.123
Rev Neurosci. 2023 Sep 01.

In vivo C6 glioma models: an update and a guide toward a more effective preclinical evaluation of potential anti-glioblastoma drugs.

Safura Pournajaf, Nastaran Afsordeh, Mohammad Hossein Pourgholami.

  Glioblastoma multiform (GBM) is the most common primary brain tumor with a poor prognosis and few therapeutic choices. In vivo, tumor models are useful for enhancing knowledge of underlying GBM pathology and developing more effective therapies/agents at the preclinical level, as they recapitulate human brain tumors. The C6 glioma cell line has been one of the most widely used cell lines in neuro-oncology research as they produce tumors that share the most similarities with human GBM regarding genetic, invasion, and expansion profiles and characteristics. This review provides an overview of the distinctive features and the different animal models produced by the C6 cell line. We also highlight specific applications of various C6 in vivo models according to the purpose of the study and offer some technical notes for more convenient/repeatable modeling. This work also includes novel findings discovered in our laboratory, which would further enhance the feasibility of the model in preclinical GBM investigations.

Keywords:  C6 cell line; glioblastoma multiform; intracranial tumor; in vivo models; subcutaneous tumor

DOI:  https://doi.org/10.1515/revneuro-2023-0067
Neuro Oncol. 2023 Aug 31. pii: noad158. [Epub ahead of print]

Epidemiology and survival of adult-type diffuse glioma in Belgium during the molecular era.

Harry Pinson, Geert Silversmit, Dimitri Vanhauwaert, Katrijn Vanschoenbeek, Jean-Pierre Kalala Okito, Steven De Vleeschouwer, Tom Boterberg, Cindy De Gendt.

   BACKGROUND: Survival data of diffuse adult-type glioma is mostly based on prospective clinical trials or small retrospective cohort studies. Real-world data with large patient cohorts is currently lacking.
METHODS: Using the nation-wide, population based Belgian Cancer Registry (BCR), all known histological reports of patients diagnosed with an adult-type diffuse glioma in Belgium between 2017 and 2019 were reviewed. The ICD-O-3 morphology codes were matched with the histological diagnosis. The gathered data was transformed into the 2021 WHO classification of CNS tumors using the IDH- and 1p/19q-mutation status.
RESULTS: Between 2017 and 2019, 2233 diffuse adult-type gliomas were diagnosed in Belgium. Full molecular status was available in 67,1% of identified cases. The age-standardized incidence rate of diffuse adult-type glioma in Belgium was estimated 8,55 per 100.000 person years and 6,72 per 100.000 person years for grade 4 lesions. Median overall survival time in IDH-wildtype glioblastoma was 9,3 months, significantly shorter compared to grade 4 IDH-mutant astrocytoma (median survival time: 25,9 months). The 3-year survival probability was 86,0% and 75,7% for grade 2 and 3 IDH-mutated astrocytoma. IDH-wildtype astrocytoma has a worse prognosis with a 3-year survival probability of 31,6% for grade 2 and 5,7% for grade 3 lesions.
CONCLUSION: This registry-based study presents a large cohort of adult-type diffuse glioma with known molecular status and uses real-world survival data. It adds to the current literature which is mainly based on historical landmark trials and smaller retrospective cohort studies.

Keywords:  diffuse adult-type glioma; epidemiology; survival

DOI:  https://doi.org/10.1093/neuonc/noad158
Acta Neuropathol Commun. 2023 08 28. 11(1): 139

MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value.

Henning Leske, Ulrike Camenisch Gross, Silvia Hofer, Marian Christoph Neidert, Sabine Leske, Michael Weller, Dirk Lehnick, Elisabeth Jane Rushing.

  Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O6-methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment.

Keywords:  Enhancer; Glioblastoma; MGMT; Prognosis; Survival; Temozolomide

DOI:  https://doi.org/10.1186/s40478-023-01622-w
Glia. 2023 Aug 28.

TREM2 promotes glioma progression and angiogenesis mediated by microglia/brain macrophages.

Xuezhen Chen, Yue Zhao, Yimin Huang, Kaichuan Zhu, Fan Zeng, Junyi Zhao, Huaqiu Zhang, Xinzhou Zhu, Helmut Kettenmann, Xianyuan Xiang.

  Triggering receptor expressed on myeloid cell 2 (TREM2), a myeloid cell-specific signaling molecule, controls essential functions of microglia and impacts on the pathogenesis of Alzheimer's disease and other neurodegenerative disorders. TREM2 is also highly expressed in tumor-associated macrophages in different types of cancer. Here, we studied whether TREM2 influences glioma progression. We found a gender-dependent effect of glioma growth in wild-type (WT) animals injected with GL261-EGFP glioma cells. Most importantly, TREM2 promotes glioma progression in male but not female animals. The accumulation of glioma-associated microglia/macrophages (GAMs) and CD31+ blood vessel density is reduced in male TREM2-deficient mice. A transcriptomic analysis of glioma tissue revealed that TREM2 deficiency suppresses immune-related genes. In an organotypic slice model devoid of functional vascularization and immune components from periphery, the tumor size was not affected by TREM2-deficiency. In human resection samples from glioblastoma, TREM2 is upregulated in GAMs. Based on the Cancer Genome Atlas Program (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases, the TREM2 expression levels were negatively correlated with survival. Thus, the TREM2-dependent crosstalk between GAMs and the vasculature formation promotes glioma growth.

Keywords:  TREM2; angiogenesis; brain tumor; glioma; macrophage; microglia; microglial cells

DOI:  https://doi.org/10.1002/glia.24456
Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad082

Spectral flow cytometry identifies distinct nonneoplastic plasma extracellular vesicle phenotype in glioblastoma patients.

Abudumijiti Zack Aibaidula, Cori E Fain, Luz Cumba Garcia, Annelise Wier, Samantha M Bouchal, Megan M Bauman, Mi-Yeon Jung, Jann N Sarkaria, Aaron J Johnson, Ian F Parney.

   Background: Glioblastoma (GBM) is the most common malignant brain tumor and has a poor prognosis. Imaging findings at diagnosis and in response to treatment are nonspecific. Developing noninvasive assays to augment imaging would be helpful. Plasma extracellular vesicles (EVs) are a promising biomarker source for this. Here, we develop spectral flow cytometry techniques that demonstrate differences in bulk plasma EV phenotype between GBM patients and normal donors that could serve as the basis of a liquid biopsy.
Methods: Plasma EVs were stained for EV-associated tetraspanins (CD9/CD63/CD81), markers indicating cell of origin (CD11b/CD31/CD41a/CD45), and actin/phalloidin (to exclude cell debris). EVs were analyzed using spectral flow cytometry. Multiparametric analysis using t-distributed stochastic neighbor embedding (t-SNE) and self-organizing maps on flow cytometry data (FlowSOM) was performed comparing GBM and normal donor (ND) plasma EVs.
Results: Size exclusion chromatography plus spectral-based flow cytometer threshold settings enriched plasma EVs while minimizing background noise. GBM patients had increased CD9+, CD63+, CD81+, and myeloid-derived (CD11b+) EVs. Multiparametric analysis demonstrated distinct surface marker expression profiles in GBM plasma EVs compared to ND EVs. Fifteen plasma EV sub-populations differing in size and surface marker expression were identified, six enriched in GBM patients and two in normal donors.
Conclusions: Multiparametric analysis demonstrates that GBM patients have a distinct nonneoplastic plasma EV phenotype compared to ND. This simple rapid analysis can be performed without purifying tumor EVs and may serve as the basis of a liquid biopsy.

Keywords:  extracellular vesicles; flow cytometry; glioblastoma; liquid biopsy

DOI:  https://doi.org/10.1093/noajnl/vdad082
Lancet Oncol. 2023 Sep;pii: S1470-2045(23)00347-9. [Epub ahead of print]24(9): 1042-1052

Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial.

Yoshie Umemura, Daniel Orringer, Larry Junck, Maria L Varela, Molly E J West, Syed M Faisal, Andrea Comba, Jason Heth, Oren Sagher, Denise Leung, Aaron Mammoser, Shawn Hervey-Jumper, Daniel Zamler, Viveka N Yadav, Patrick Dunn, Wajd Al-Holou, Todd Hollon, Michelle M Kim, Daniel R Wahl, Sandra Camelo-Piragua, Andrew P Lieberman, Sriram Venneti, Paul McKeever, Theodore Lawrence, Ryo Kurokawa, Karen Sagher, David Altshuler, Lili Zhao, Karin Muraszko, Maria G Castro, Pedro R Lowenstein.

BACKGROUND: High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma.
METHODS: In this dose-finding, first-in-human trial, treatment-naive adults aged 18-75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992.
FINDINGS: Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1).
INTERPRETATION: The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial.
FUNDING: Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan.

DOI: https://doi.org/10.1016/S1470-2045(23)00347-9
JCI Insight. 2023 Aug 31. pii: e171225. [Epub ahead of print]

Altered plasma metabolite levels can be detected years before a glioma diagnosis.

Sebastian Löding, Ulrika Andersson, Rudolf Kaaks, Matthias B Schulze, Valeria Pala, Ilona Urbarova, Pilar Amiano, Sandra M Colorado-Yohar, Marcela Guevara, Alicia K Heath, Anastasia Chrysovalantou Chatziioannou, Mattias Johansson, Lars Nyberg, Henrik Antti, Benny Björkblom, Beatrice Melin.

  Genetic and metabolic changes in tissue and blood are reported to occur several years before glioma diagnosis. As gliomas are currently detected late, a liquid biopsy for early detection could impact the quality of life and prognosis of patients. Here, we present a nested case-control study of 550 pre-diagnostic glioma cases and 550 healthy controls, from the Northern Sweden Health and Disease study (NSHDS) and the European Prospective Investigation into Cancer and Nutrition (EPIC) study. We identified 93 significantly altered metabolites related to glioma development up to eight years before diagnosis. Out of these metabolites, a panel of 20 selected metabolites showed strong disease correlation and consistent progression pattern towards diagnosis in both the NSHDS and EPIC cohorts, and separated favorably future cases from controls independently of biological sex. The blood metabolite panel also successfully separated both lower grade glioma and glioblastoma cases from controls, up to eight years before diagnosis in NSHDS (glioma AUC=0.85, P=3.1e-12; glioblastoma AUC=0.85, P=6.3e-8), and up to two years before diagnosis in EPIC (glioma AUC=0.81, P=0.005; glioblastoma AUC=0.89, P=0.04). Pathway enrichment analysis detected metabolites related to the TCA-cycle, Warburg effect, gluconeogenesis, cysteine-, pyruvate- and tyrosine metabolism as the most affected.

Keywords:  Brain cancer; Metabolism; Oncology

DOI:  https://doi.org/10.1172/jci.insight.171225
Nat Cancer. 2023 Aug 31.

Myeloid-specific KDM6B inhibition sensitizes glioblastoma to PD1 blockade.

Sangeeta Goswami, Deblina Raychaudhuri, Pratishtha Singh, Seanu Meena Natarajan, Yulong Chen, Candice Poon, Mercedes Hennessey, Aminah J Tannir, Jan Zhang, Swetha Anandhan, Brittany Parker Kerrigan, Marc D Macaluso, Zhong He, Sonali Jindal, Frederick F Lang, Sreyashi Basu, Padmanee Sharma.

Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme-histone 3 lysine 27 demethylase (KDM6B)-in intratumoral immune-suppressive myeloid cell subsets. Importantly, myeloid cell-specific Kdm6b deletion enhanced proinflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies showed that the absence of Kdm6b enhances antigen presentation, interferon response and phagocytosis in myeloid cells by inhibition of mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b-deleted myeloid cells and enhanced anti-PD1 efficacy. This study thus identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target for enhanced response to ICT.

DOI: https://doi.org/10.1038/s43018-023-00620-0
Neuro Oncol. 2023 Aug 31. pii: noad159. [Epub ahead of print]

EPIC-1042 as a potent PTRF/Cavin1-Caveolin-1 interaction inhibitor to induce PARP1 autophagic degradation and suppress temozolomide efflux for Glioblastoma.

Biao Hong, Eryan Yang, Dongyuan Su, Jiasheng Ju, Xiaoteng Cui, Qixue Wang, Fei Tong, Jixing Zhao, Shixue Yang, Chunchao Cheng, Lei Xin, Menglin Xiao, Kaikai Yi, Qi Zhan, Yaqing Ding, Hanyi Xu, Longtao Cui, Chunsheng Kang.

   BACKGROUND: Temozolomide (TMZ) treatment efficacy in glioblastoma is determined by various mechanisms such as TMZ efflux, autophagy, base excision repair (BER) pathway, and the level of O 6-methylguanine-DNA methyltransferase (MGMT). Here, we reported a novel small-molecular inhibitor (SMI) EPIC-1042 (C20H28N6) with the potential to decrease TMZ efflux and promote PARP1 degradation via autolysosomes in the early stage.
METHODS: EPIC-1042 was obtained from Receptor-based virtual screening. Co-immunoprecipitation and pull-down assays were applied to verify the blocking effect of EPIC-1042. Western blotting, Co-immunoprecipitation and immunofluorescence were used to elucidate the underlying mechanisms of EPIC-1042. In vivo experiments were performed to verify the efficacy of EPIC-1042 in sensitizing glioblastoma cells to TMZ.
RESULTS: EPIC-1042 physically interrupted the interaction of PTRF/Cavin1 and caveolin-1, leading to reduced secretion of small extracellular vesicles (sEVs) to decrease TMZ efflux. It also induced PARP1 autophagic degradation via increased p62 expression that more p62 bound to PARP1 and specially promoted PARP1 translocation into autolysosomes for degradation in the early stage. Moreover, EPIC-1042 inhibited autophagy flux at last. The application of EPIC-1042 enhanced TMZ efficacy in glioblastoma in vivo.
CONCLUSION: EPIC-1042 reinforced the effect of TMZ by preventing TMZ efflux, inducing PARP1 degradation via autolysosomes to perturb the BER pathway and recruitment of MGMT, and inhibiting autophagy flux in the later stage. Therefore, this study provided a novel therapeutic strategy using the combination of TMZ with EPIC-1042 for glioblastoma treatment.

Keywords:  Autophagy; PARP1; Small-Molecular Inhibitor; TMZ efficacy; TMZ efflux

DOI:  https://doi.org/10.1093/neuonc/noad159
Lancet Oncol. 2023 Sep;pii: S1470-2045(23)00389-3. [Epub ahead of print]24(9): 949-950

Combined gene therapies for high-grade glioma.

Joshua D Bernstock, Alexander Ling, E Antonio Chiocca.

DOI: https://doi.org/10.1016/S1470-2045(23)00389-3
J Clin Invest. 2023 Sep 01. pii: e169314. [Epub ahead of print]133(17):

Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain tumors.

Lu Sun, Jenny C Kienzler, Jeremy G Reynoso, Alexander Lee, Eileen Shiuan, Shanpeng Li, Jiyoon Kim, Lizhong Ding, Amber J Monteleone, Geoffrey C Owens, Joanna J Phillips, Richard G Everson, David Nathanson, Timothy F Cloughesy, Gang Li, Linda M Liau, Willy Hugo, Won Kim, Robert M Prins.

  In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well studied. Here, we present an integrated single-cell RNA-Seq (scRNA-Seq) study of 19 ICB-naive and 9 ICB-treated BrM samples from our own and published data sets. We compared them with our previously published scRNA-Seq data from rGBM and found that ICB led to more prominent T cell infiltration into BrM than rGBM. These BrM-infiltrating T cells exhibited a tumor-specific phenotype and displayed greater activated/exhausted features. We also used multiplex immunofluorescence and spatial transcriptomics to reveal that ICB reduced a distinct CD206+ macrophage population in the perivascular space, which may modulate T cell entry into BrM. Furthermore, we identified a subset of progenitor exhausted T cells that correlated with longer overall survival in BrM patients. Our study provides a comprehensive immune cellular landscape of ICB's effect on metastatic brain tumors and offers insights into potential strategies for improving ICB efficacy for brain tumor patients.

Keywords:  Brain cancer; Cancer immunotherapy; Immunology; Neuroscience

DOI:  https://doi.org/10.1172/JCI169314
J Clin Oncol. 2023 Aug 29. JCO2300558

Phase II Trial of Dabrafenib Plus Trametinib in Relapsed/Refractory BRAF V600-Mutant Pediatric High-Grade Glioma.

all the Investigators involved in the high-grade glioma cohort

PURPOSE: BRAF V600 mutation is detected in 5%-10% of pediatric high-grade gliomas (pHGGs), and effective treatments are limited. In previous trials, dabrafenib as monotherapy or in combination with trametinib demonstrated activity in children and adults with relapsed/refractory BRAF V600-mutant HGG.
METHODS: This phase II study evaluated dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600-mutant pHGG. The primary objective was overall response rate (ORR) by independent review by Response Assessment in Neuro-Oncology criteria. Secondary objectives included ORR by investigator determination, duration of response (DOR), progression-free survival, overall survival (OS), and safety.
RESULTS: A total of 41 pediatric patients with previously treated BRAF V600-mutant HGG were enrolled. At primary analysis, median follow-up was 25.1 months, and 51% of patients remained on treatment. Sixteen of 20 discontinuations were due to progressive disease in this relapsed/refractory pHGG population. Independently assessed ORR was 56% (95% CI, 40 to 72). Median DOR was 22.2 months (95% CI, 7.6 months to not reached [NR]). Fourteen deaths were reported. Median OS was 32.8 months (95% CI, 19.2 months to NR). The most common all-cause adverse events (AEs) were pyrexia (51%), headache (34%), and dry skin (32%). Two patients (5%) had AEs (both rash) leading to discontinuation.
CONCLUSION: In relapsed/refractory BRAF V600-mutant pHGG, dabrafenib plus trametinib improved ORR versus previous trials of chemotherapy in molecularly unselected patients with pHGG and was associated with durable responses and encouraging survival. These findings suggest that dabrafenib plus trametinib is a promising targeted therapy option for children and adolescents with relapsed/refractory BRAF V600-mutant HGG.

DOI: https://doi.org/10.1200/JCO.23.00558