Abstract
In spite of major recent advances in diffuse intrinsic pontine glioma (DIPG) molecular characterization, this body of knowledge has not yet translated into better treatments. To date, more than 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy as well as newer biologic agents have failed to improve the dismal outcome when compared to palliative radiation alone. The biology of DIPG remained unknown until recently when the neurosurgical expertise along with the recognition by the scientific and clinical community of the importance of tissue sampling at diagnosis; ideally, in the context of a clinical trial and by trained neurosurgical teams to maximize patient safety. These pre-treatment tumor samples, and others coming from tissue obtained post-mortem, have yielded new insights into DIPG molecular pathogenesis. We now know that DIPG comprises a heterogeneous disease with variable molecular phenotypes, different from adult high-grade glioma, other non-pontine pediatric high-grade gliomas, and even between pontine gliomas. The discovery of histone H3.3 or H3.1 mutations has been an important step forward in understanding tumor formation, maintenance, and progression. Pharmacologic reversal of DIPG histone demethylation therefore offers an important potential intervention strategy for the treatment of DIPG. To date, clinical trials of newly diagnosed or progressive DIPG with epigenetic (histone) modifiers have been unsuccessful. Whether this failure represents limited activity of the agents used, their CNS penetration, redundant pathways within the tumor, or the possibility that histone mutations are necessary only to initiate DIPGs but not maintain their growth, suggest that a great deal still needs to be elucidated in both the underlying biology of these pathways and the drugs designed to target them. In this review, we will discuss the role of both epigenetic and genetic mutations within DIPG and the development of treatment strategies directed against the unique abnormalities present in this disease.
Highlights
Diffuse intrinsic pontine glioma (DIPG), the most frequent brainstem tumor in pediatrics, is one of the deadliest cancers among children
It is well known that the introduction of the H3.3K27M mutation into p53-null and nestin-expressing progenitors in the neonatal mouse brainstem is unable to generate gliomas, it is sufficient to induce ectopic cell clusters in the mouse brain. This has led different groups to focus on the role that these epigenetic alterations play in diffuse intrinsic pontine glioma (DIPG) initiation versus maintenance or proliferation [10, 12, 17, 18, 22]
The use of the GSKJ4, an inhibitor of JMJD3 H3K27 demethylase in K27Mexpressing cells revealed a dose-dependent inhibition of cellular viability, with 50% growth inhibition
Summary
Diffuse intrinsic pontine glioma (DIPG), the most frequent brainstem tumor in pediatrics, is one of the deadliest cancers among children. Diagnosis has been based on classic clinical and radiological presentation, with “no indication” for histologic confirmation in the vast majority of cases [1]. This practice – with obvious absence of tumor tissue at diagnosis to study – has. More than 250 clinical trials including standard chemotherapeutic agents administered in different intensities and timings, biologic and targeted agents, immunotherapy, etc., along with radiation therapy have not significantly improved the event free survival (EFS) or overall survival (OS) of patients with DIPG [2]. With the increasing biologic data, we have on DIPG, the scientific and clinical communities have the ability to start selecting more rationale treatment options that take into account the underlying pathways driving these tumors, the penetration of drugs into the tumor and the potential resistance pathways generated by the tumor [5]
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