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Table of Contents    
Year : 2023  |  Volume : 71  |  Issue : 1  |  Page : 2-4

Diffuse Intrinsic Pontine Gliomas: Will there Ever be a Light at the End of the Dark Tunnel?

Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication24-Feb-2023

Correspondence Address:
Prof. P Sarat Chandra
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.314592

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How to cite this article:
Chandra P S. Diffuse Intrinsic Pontine Gliomas: Will there Ever be a Light at the End of the Dark Tunnel?. Neurol India 2023;71:2-4

How to cite this URL:
Chandra P S. Diffuse Intrinsic Pontine Gliomas: Will there Ever be a Light at the End of the Dark Tunnel?. Neurol India [serial online] 2023 [cited 2023 Mar 25];71:2-4. Available from: https://www.neurologyindia.com/text.asp?2023/71/1/2/314592

The editorial team of Neurology India wishes all its readers a very happy new year for 2023. The year unfolds with hope at the receding end of the deadly COVID pandemic, and we all hope that we have all seen the last of it.

Neurology India has also faced several challenges in the past few years. These include the change of the operating platform. We are happy to inform the readers that we are now using the Editorial manager as its operating platform.

Plans are also afoot to launch a new sister journal, “Neurology India- Case Reports.” This should hopefully address the large submissions of case reports to the journal. Case reports still form a powerful platform for new knowledge dissipation and a medium for publication for several young authors. Neurology India is one of the few journals which has always encouraged the publication of several case reports in its issues. However, due to the increasing burden of case report submissions, we have decided to address this long-pending need to create a separate sister journal.

One of the pathologies that bring about the greatest sense of despair, helplessness, and an ominous feeling is diffuse intrinsic pontine glioma (DIPG). The diagnosis is usually straightforward, being clinical-radiological, and often brings about a “sinking feeling” in the clinician on visualizing the MRI scans. The patients are generally children, often around 8–12 years of age, usually presenting with minor complaints. The MRI almost entirely clinches the diagnosis. A complete workup is, of course, mandatory, performing contrast studies, MR spectroscopy, tractography, etc. Differential diagnosis is very limited. Tuberculoma is to be kept in mind in our country, although I have never seen the diagnosis of DIPG being ever inaccurate. However, to adhere to clinical esthetics, we may consider the following: differential diagnostic considerations include non-malignant brainstem entities, including low-grade glioma, primitive neuroectodermal tumor (PNET), vascular malformations, encephalitic parenchymal lesions, cysts, and demyelinating disorders.

DIPG has been universally such a challenging pathology to treat; most have almost given up any hope of finding a cure for this disease, although there is a significant amount of research ongoing.

The current treatment options for DIPG are limited, and the prognosis is dismal—with less than 10% of patients surviving beyond 2.[1] DIPGs represent 80% of all pediatric brain tumors in the brainstem.[2] Histologically, these tumors share features with anaplastic astrocytomas (grade III) or glioblastomas (GBM) (grade IV). Under the World Health Organization 2016 classification of brain tumors, pediatric gliomas with a K27M mutation in histone H3 (3.1 or 3.3) with a diffuse growth pattern in a midline location are termed diffuse midline glioma, H3 K27M mutant; this designation is inclusive of DIPG cases bearing the K27M mutation.[3],[4]

Molecular subtyping has allowed us to understand the nature of this pathology. The hope of curing this disease will likely be advanced molecular, immunological, and genetic methodologies.

DIPGs can be subclassified into three distinct molecularly defined groups: H3K27M, MYCN, and silent. While there are similarities between DIPG and high-grade glioma, it is now recognized as a unique entity with distinct genomic and molecular alterations. To cite one difference, H3 mutations are present in over 80% of DIPG's, while only 35% of pediatric non-brainstem high-grade gliomas have them. In addition, histone mutations are present in most DIPG tumors and identifying these mutations has resulted in a paradigm shift that has redefined our focus on research and clinical management.[5]

Some of the recent developments have brought some hope to this invariably fatal disease. Multiple therapeutic avenues for DIPG seem encouraging. These include targeted therapies, epigenetic therapy, and immunotherapy. More recently, viral particle therapy also showed some promise.

Since the development of targeted therapies for DIPG, approximately 250 clinical trials have been initiated against different biological pathways in the disease. The most commonly amplified gene is PDGFRA, found in 10% of DIPGs. Not surprisingly, PDGFRA is one of the most targeted genes for therapy in DIPG. However, in clinical trials, agents targeting PDGFR, such as imatinib and dasatinib, have exhibited relatively poor antitumor effects. Another gene targeted in DIPG is EGFR, which has also been shown to be overexpressed in pediatric brain tumors. Clinical trials of anti-EGFR drugs, including nimotuzumab, gefitinib, and erlotinib, have shown some benefit in small subsets of DIPG patients. Other trials have used PARP1 inhibitors (olaparib, niraparib, and veliparib), CDK4/CDK6 inhibitors (PD-0332991), WEE1 kinase inhibitor (MK1775), and the angiogenesis inhibitor (bevacizumab). Despite various clinical trial attempts, none have shown significant efficacy in DIPG. We, of course, do not know if these drugs cross the blood–brain barrier (BBB).[6],[7],[8]

The current standard of care for DIPGs consists of standard fractionated radiation alone to a dose of 54–59 Gy, as surgical resection is not feasible in DIPG.[9] However, most treatment regimens, including monotherapy and combination chemotherapies, have thus far yielded no substantial benefit.

In the interesting paper published in the same issue, a cohort of 184 patients (ages 6–11; median 8 years) with DIPG was studied between 2015 and 2019. About 75.2% of patients completed their first radiotherapy treatment, of which only 5% and 6% had worsening clinical symptoms and persistent need for steroids post-treatment 1-month. On multivariate analysis, Lansky performance status <60 (p = 0.028), cranial Nerve IX, and X (p = 0.026) involvement were associated with poor survival, while those receiving radiotherapy were associated with better survival (p < 0.001). In the cohort of patients receiving radiotherapy, only those receiving repeat radiotherapy were associated with improved survival (p = 0.002). The median progression-free survival (PFS) and overall survival (OS) were 6.6 months (95% CI 5.5-7.7 months SE: 0.54) and 9.4 months (95% CI 6.5-12.5, SE: 1.4), respectively for the whole cohort. The OS at 12 and 24 months were 46.6% and 7.2%, respectively.[10]

Recent advances in the field of immunotherapy, however, have identified a potential role for anti-GD2 chimeric antigen receptor (CAR) T-cell therapy, which may show potential efficacy. These limited treatment options highlight the need for novel therapeutic approaches. Herein we describe possible targets and common obstacles to effective therapies.

Various oncogenic drivers and somatic mutations in DIPG contribute to its rapid tumorigenesis and dismal outcomes. As previously mentioned, the most common mutation involves the substitution of a lysine for methionine at position 27 in histone H3, particularly in histone 3.1 and 3.3, which is associated with a worse prognosis over their wild-type counterparts. DIPGs tend to have either a somatic mutation in H3K27M and/or a global loss of H3K27 trimethylation; this is suggested to be one of the oncogenic drivers of this disease. The presence of H3K27M leads to various downstream chromatin remodeling cascades, epigenetic silencing, and activation of multiple genes and pathways. Identifying this mutation and discoveries of subsequent secondary mutations open the door to druggable targets such as histone deacetylase (HDAC) and demethylase inhibitors—some of which have shown promising results.[11],[12],[13]

Previously, one of the most common obstacles regarding DIPG research and target identification was the lack of available tumor tissue. However, with the increasing acquisition of post-mortem tissues and biopsies, several molecular studies can now be performed robustly and reproducibly. As a result, many promising targets have been identified, and several drugs have shown efficacy in the preclinical setting. However, there remains a considerable obstacle between clinical application and drug discovery due to the lack of effective drug delivery across an intact blood–brain barrier (BBB). This may also explain why drugs that show efficacy in other gliomas have failed in DIPG.[8] Therefore, improving drug delivery due to structural adaptation or physical disruption of the BBB will be vital for novel therapies to be translated into the clinic.

Lastly, the tumor microenvironment is a critical component of the tumor to consider when deciding on treatment, particularly immunotherapy. Recent studies have concluded that DIPGs possess a non-inflammatory tumor microenvironment.[14] However, whether DIPG tumors contain tumor-associated macrophages have yet to be thoroughly investigated, as conflicting results state that DIPGs do not have increased macrophage infiltration. However, most studies have demonstrated no T-cell infiltration in DIPG. Hence, it is evident that immunotherapeutic approaches should be focused on the recruitment or introduction of immune cells to the tumor.

More recently, the introduction of viral particles (dnx-2401) has shown some benefit in DIPG, although it has been performed in a small cohort.

A cohort of 12 patients, 3–18 years of age, with newly diagnosed DIPG received viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in one patient each. Over a median follow-up of 17.8 months (range, 5.9–33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in nine patients, a partial response in three patients, and stable disease in eight patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, one of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from one patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire.[15]

Summarizing, it is clear that surgical strategies are of little use for DIPG. The promise lies in developing unique medical oncological strategies. Currently, radiotherapy and repeat radiotherapy seem to be the only viable option.

 » References Top

Warren KE. Diffuse intrinsic pontine glioma: Poised for progress. Front Oncol 2012;2:205.  Back to cited text no. 1
Srikanthan D, Taccone MS, Van Ommeren R, Ishida J, Krumholtz SL, Rutka JT. Diffuse intrinsic pontine glioma: Current insights and future directions. Chin Neurosurg J 2021;7:6.  Back to cited text no. 2
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro Oncol 2021;23:1231-51.  Back to cited text no. 3
Jansen MH, Veldhuijzen van Zanten SE, Heymans MW, Hargrave D, Kramm CM, Van Vuurden DG. Commentary on “Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes”. Acta Neuropathol 2016;131:793-794.  Back to cited text no. 4
Castel D, Philippe C, Calmon R, Le Dret L, Truffaux N, Boddaert N, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 2015;130:815-27.  Back to cited text no. 5
Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 2010;28:3061-8.  Back to cited text no. 6
Gilbertson RJ, Bentley L, Hernan R, Junttila TT, Frank AJ, Haapasalo H, et al. ERBB receptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease. Clin Cancer Res 2002;8:3054-64.  Back to cited text no. 7
Veringa SJ, Biesmans D, van Vuurden DG, Jansen MH, Wedekind LE, Horsman I, et al. In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma. PLoS One 2013;8:e61512.  Back to cited text no. 8
Frazier JL, Lee J, Thomale UW, Noggle JC, Cohen KJ, Jallo GI. Treatment of diffuse intrinsic brainstem gliomas: Failed approaches and future strategies. J Neurosurg Pediatr 2009;3:259-269.  Back to cited text no. 9
Krishnatry R, Mani S, Manjali JJ, Rane PP, Chatterjee A, Goda JS, et al. Institutional Patterns of Care of Diffuse Intrinsic Pontine Glioma. Neurol India 2022;71:72-8.  Back to cited text no. 10
Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 2012;44:251-3.  Back to cited text no. 11
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. J Neurosurg Pediatr 2018;23:308-316.  Back to cited text no. 12
Kim TW, Kang BH, Jang H, Kwak S, Shin J, Kim H, et al. Ctbp2 modulates NuRD-mediated deacetylation of H3K27 and facilitates PRC2-mediated H3K27me3 in active embryonic stem cell genes during exit from pluripotency. Stem Cells 2015;33:2442-55.  Back to cited text no. 13
Lieberman NAP, DeGolier K, Kovar HM, Davis A, Hoglund V, Stevens J, et al. Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: Implications for development of immunotherapy. Neuro Oncol 2019;21:83-94.  Back to cited text no. 14
Gallego Perez-Larraya J, Garcia-Moure M, Labiano S, Patino-Garcia A, Dobbs J, Gonzalez-Huarriz M, et al. Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma. N Engl J Med 2022;386:2471-2481.  Back to cited text no. 15


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