Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.

Central European Institute of Technology Masaryk University Brno Czechia

Comprehensive Cancer Center Vienna Medical University of Vienna Vienna Austria

Department of Biomedical Imaging and Image Guided Therapy Medical University of Vienna Vienna Austria

Department of Neurosurgery Medical University of Vienna Vienna Austria

Department of Neurosurgery University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

Department of Pathology Faculty Hospital Brno Brno Czechia

Department of Pediatric Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

Department of Pediatric Radiology University Hospital Brno and Faculty of Medicine Masaryk University Vienna Czechia

Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics Medical University of Vienna Vienna Austria

Institute of Neurology Medical University of Vienna Vienna Austria

International Clinical Research Center St Anne's University Hospital Brno Czechia

Laboratory of Tumor Biology Department of Experimental Biology School of Science Masaryk University Brno Czechia

Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czechia

Zobrazit více v PubMed

Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky Y, Kruchko C, Barnholtz-Sloan J. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2005–2009. Neuro Oncol. (2015) 17 (Suppl. 4):iv1–62. 10.1093/neuonc/nov189 PubMed DOI PMC

Sturm D, Bender S, Jones DTW, Lichter P, Grill J, Becher O, et al. . Paediatric and adult glioblastoma: Multiform (epi)genomic culprits emerge. Nat Rev Cancer. (2014) 14:92–107. 10.1038/nrc3655 PubMed DOI PMC

Schwartzentruber J, Korshunov A, Liu XY, Jones DTW, Pfaff E, Jacob K, et al. . Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. (2012) 482:226–31. 10.1038/nature10833 PubMed DOI

Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y, et al. . The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet. (2014) 46:444–50. 10.1038/ng.2938 PubMed DOI PMC

Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, et al. . K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. (2012) 124:439–47. 10.1007/s00401-012-0998-0 PubMed DOI PMC

Jansen MH, Van Zanten SEV, Aliaga ES, Heymans MW, Warmuth-Metz M, Hargrave D, et al. . Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria. Neuro Oncol. (2015) 17:160–6. 10.1093/neuonc/nou104 PubMed DOI PMC

Hoffman LM, Van Zanten SEMV, Colditz N, Baugh J, Chaney B, Hoffmann M, et al. . Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of Diffuse Intrinsic Pontine Glioma (DIPG): a collaborative report from the international and european society for pediatric oncology DIPG registries. J Clin Oncol. (2018) 36:1963–72. 10.1200/JCO.2017.75.9308 PubMed DOI PMC

Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, et al. . Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell. (2017) 32:520–37.e5. 10.1016/j.ccell.2017.08.017 PubMed DOI PMC

Lu VM, Alvi MA, Mcdonald KL, Daniels DJ. Impact of the H3K27M mutation on survival in pediatric high-grade glioma: a systematic review and meta-analysis. (2019) 23:308–16. 10.3171/2018.9.PEDS18419 PubMed DOI

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. . The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. (2016)803–20. 10.1007/s00401-016-1545-1 PubMed DOI

Wagner S, Warmuth-Metz M, Emser A, Gnekow AK, Sträter R, Rutkowski S, et al. . Treatment options in childhood pontine gliomas. J Neurooncol. (2006) 79:281–7. 10.1007/s11060-006-9133-1 PubMed DOI

El-Khouly FE, Veldhuijzen van Zanten SEM, Santa-Maria Lopez V, Hendrikse NH, Kaspers GJL, Loizos G, et al. . Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand? J Neurooncol. (2019) 145:177–84. 10.1007/s11060-019-03287-9 PubMed DOI PMC

Massimino M, Biassoni V, Miceli R, Schiavello E, Warmuth-Metz M, Modena P, et al. . Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood. J Neurooncol. (2014) 118:305–12. 10.1007/s11060-014-1428-z PubMed DOI

Cohen KJ, Heideman RL, Zhou T, Holmes EJ, Lavey RS, Bouffet E, Pollack IF. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group. Neuro Oncol. (2011) 13:410–6. 10.1093/neuonc/noq205 PubMed DOI PMC

Gokce-Samar Z, Beuriat PA, Faure-Conter C, Carrie C, Chabaud S, Claude L, et al. . Pre-radiation chemotherapy improves survival in pediatric diffuse intrinsic pontine gliomas. Child Nerv Syst. (2016) 32:1415–23. 10.1007/s00381-016-3153-8 PubMed DOI

Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, et al. . Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet. (2014) 46:451–6. 10.1038/ng.2936 PubMed DOI PMC

Jones C, Baker SJ. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat Rev Cancer. (2014) 14:651–61. 10.1038/nrc3811 PubMed DOI PMC

Ryall S, Krishnatry R, Arnoldo A, Buczkowicz P, Mistry M, Siddaway R, et al. . Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma. Acta Neuropathol Commun. (2016) 4:93. 10.1186/s40478-016-0353-0 PubMed DOI PMC

Filbin MG, Tirosh I, Hovestadt V, Shaw ML, Escalante LE, Mathewson ND, et al. . Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq. Science. (2018) 360:331–5. 10.1126/science.aao4750 PubMed DOI PMC

Hoffman LM, DeWire M, Ryall S, Buczkowicz P, Leach J, Miles L, et al. Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun. (2016) 4:1 10.1186/s40478-015-0269-0 PubMed DOI PMC

Ochs K, Ott M, Bunse T, Sahm F, Bunse L, Deumelandt K, et al. . K27M-mutant histone-3 as a novel target for glioma immunotherapy. Oncoimmunology. (2017) 6:1–7. 10.1080/2162402X.2017.1328340 PubMed DOI PMC

Geoerger B, Hargrave D, Thomas F, Ndiaye A, Frappaz D, Andreiuolo F, et al. . Innovative Therapies for Children with Cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors. Neuro Oncol. (2011) 13:109–18. 10.1093/neuonc/noq141 PubMed DOI PMC

Pollack IF, Stewart CF, Kocak M, Poussaint TY, Broniscer A, Banerjee A, et al. . A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the pediatric brain tumor consortium. Neuro Oncol. (2011) 13:290–7. 10.1093/neuonc/noq199 PubMed DOI PMC

Bartels U, Wolff J, Gore L, Dunkel I, Gilheeney S, Allen J, et al. . Phase 2 study of safety and efficacy of nimotuzumab in pediatric Patients with progressive diffuse intrinsic pontine glioma. Neuro Oncol. (2014) 16:1554–9. 10.1093/neuonc/nou091 PubMed DOI PMC

Broniscer A, Jia S, Mandrell B, Hamideh D, Huang J, Onar-Thomas A, et al. . Phase 1 trial, pharmacokinetics, and pharmacodynamics of dasatinib combined with crizotinib in children with recurrent or progressive high-grade and diffuse intrinsic pontine glioma. Pediatr Blood Cancer. (2018) 65:1–8. 10.1002/pbc.27035 PubMed DOI PMC

Gajjar A, Pfister SM, Taylor MD, Gilbertson RJ. Molecular insights into pediatric brain tumors have the potential to transform therapy. Clin Cancer Res. (2014) 20:5630–40. 10.1158/1078-0432.CCR-14-0833 PubMed DOI PMC

Miklja Z, Pasternak A, Stallard S, Nicolaides T, Kline-Nunnally C, Cole B, et al. Molecular profiling and targeted therapy in pediatric gliomas: review and consensus recommendations. Neuro Oncol. (2019) 21:noz022 10.1093/neuonc/noz022 PubMed DOI PMC

Gröbner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, et al. . The landscape of genomic alterations across childhood cancers. Nature. (2018) 555:321–7. 10.1038/nature25480 PubMed DOI

Pfaff E, El Damaty A, Balasubramanian GP, Blattner-Johnson M, Worst BC, Stark S, et al. . Brainstem biopsy in pediatric diffuse intrinsic pontine glioma in the era of precision medicine: the INFORM study experience. Eur J Cancer. (2019) 114:27–35. 10.1016/j.ejca.2019.03.019 PubMed DOI

Mueller S, Jain P, Liang WS, Kilburn L, Kline C, Gupta N, et al. . A pilot precision medicine trial for children with diffuse intrinsic pontine glioma—PNOC003: a report from the pacific pediatric neuro-oncology consortium. Int J Cancer. (2019) 145:1889–901. 10.1002/ijc.32258 PubMed DOI

Bhutani J, Sheikh A, Niazi AK. Akt inhibitors: mechanism of action and implications for anticancer therapeutics. Infect Agent Cancer. (2013) 8:12–5. 10.1186/1750-9378-8-49 PubMed DOI PMC

Romano G, Chen PL, Song P, McQuade JL, Liang RJ, Liu M, et al. A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling. Cancer Discov. (2018) 8:556–67. 10.1158/2159-8290.CD-17-0745 PubMed DOI PMC

Han HJ, Jain P, Resnick AC. Shared ACVR1 mutations in FOP and DIPG: opportunities and challenges in extending biological and clinical implications across rare diseases. Bone. (2017) 109:91–100. 10.1016/j.bone.2017.08.001 PubMed DOI PMC

Bouffet E, Larouche V, Campbell BB, Merico D, De Borja R, Aronson M, et al. . Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol. (2016) 34:2206–11. 10.1200/JCO.2016.66.6552 PubMed DOI

Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. . DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. (2018) 46:D1074–82. 10.1093/nar/gkx1037 PubMed DOI PMC

Bangi E, Ang C, Smibert P, Uzilov AV, Teague AG, Antipin Y, et al. . A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer. Sci Adv. (2019) 5:1–12. 10.1126/sciadv.aav6528 PubMed DOI PMC

Burger MC, Ronellenfitsch MW, Lorenz NI, Wagner M, Voss M, Capper D, et al. . Dabrafenib in patients with recurrent, BRAF V600E mutated malignant glioma and leptomeningeal disease. Oncol Rep. (2017) 38:3291–6. 10.1093/neuonc/nox168.877 PubMed DOI PMC

Grossauer S, Koeck K, Murphy NE, Meyers ID, Daynac M, Truffaux N, et al. . Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model. Oncotarget. (2016) 7:75839–53. 10.18632/oncotarget.12419 PubMed DOI PMC

Chamberlain MC. Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series. J Neurooncol. (2013) 114:237–40. 10.1007/s11060-013-1176-5 PubMed DOI

Cappellano AM, Senerchia AA, Adolfo F, Paiva PM, Pinho R, Covic A, et al. . Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex. Child Nerv Syst. (2013) 29:2301–5. 10.1007/s00381-013-2170-0 PubMed DOI

Salomon G, Maza A, Boulinguez S, Paul C, Lamant L, Tournier E, et al. . Efficacy of anti-programmed cell death-1 immunotherapy for skin carcinomas and melanoma metastases in a patient with xeroderma pigmentosum. Br J Dermatol. (2018) 178:1199–203. 10.1111/bjd.16270 PubMed DOI

Worst BC, van Tilburg CM, Balasubramanian GP, Fiesel P, Witt R, Freitag A, et al. . Next-generation personalised medicine for high-risk paediatric cancer patients – The INFORM pilot study. Eur J Cancer. (2016) 65:91–101. 10.1016/j.ejca.2016.06.009 PubMed DOI

Jaspan XT, Morgan XPS, Warmuth-Metz XM, Sanchez Aliaga XE, Warren XD, Calmon XR, et al. Response assessment in pediatric neuro-oncology: implementation and expansion of the RANO criteria in a randomized phase II trial of pediatric patients with newly diagnosed high-grade gliomas ABBREVIATIONS: HERBY a study of avastin (bevacizumab) in combin. (2016) 37:1581–7. 10.3174/ajnr.A4782 PubMed DOI PMC

Mistry M, Zhukova N, Merico D, Rakopoulos P, Krishnatry R, Shago M, et al. . BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol. (2015) 33:1015–22. 10.1200/JCO.2014.58.3922 PubMed DOI PMC

Nakano Y, Yamasaki K, Sakamoto H, Matsusaka Y, Kunihiro N, Fukushima H, et al. . A long-term survivor of pediatric midline glioma with H3F3A K27M and BRAF V600E double mutations. Brain Tumor Pathol. (2019) 36:162–8. 10.1007/s10014-019-00347-w PubMed DOI

Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, et al. . Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet. (2014) 46:457–61. 10.1038/ng.2925 PubMed DOI PMC

Englinger B, Pirker C, Heffeter P, Terenzi A, Kowol CR, Keppler BK, et al. . Metal drugs and the anticancer immune response. Chem Rev. (2019) 119, 1519–624. 10.1021/acs.chemrev.8b00396 PubMed DOI

Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, et al. . Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. (2019) 25:477–86. 10.1038/s41591-018-0337-7 PubMed DOI PMC

Iwamoto FM, Lamborn KR, Robins HI, Mehta MP, Chang SM, Butowski NA, et al. . Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro Oncol. (2010) 12:855–61. 10.1093/neuonc/noq025 PubMed DOI PMC

Hall MD, Odia Y, Allen JE, Tarapore R, Khatib Z, Niazi TN, et al. First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M–mutant pediatric diffuse intrinsic pontine glioma: a case report. J Neurosurg Pediatr. (2019) 23:1–7. 10.3171/2019.2.PEDS18480 PubMed DOI

Ishizawa J, Zarabi SF, Davis RE, Halgas O, Nii T, Jitkova Y, et al. . Mitochondrial ClpP-mediated proteolysis induces selective cancer cell lethality. Cancer Cell. (2019) 35:721–37.e9. 10.1016/j.ccell.2019.03.014 PubMed DOI PMC

Stallard S, Savelieff MG, Wierzbicki K, Mullan B, Miklja Z, Bruzek A, et al. . CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response. Acta Neuropathol Commun. (2018) 6:7–10. 10.1186/s40478-018-0580-7 PubMed DOI PMC

Detection of H3F3A K27M or BRAF V600E in liquid biopsies of brain tumor patients as diagnostic and monitoring biomarker: impact of tumor localization and sampling method

Detection of cell-free histones in the cerebrospinal fluid of pediatric central nervous system malignancies by imaging flow cytometry