Diffuse Intrinsic Pontine Glioma: Clinical Features and Ongoing Discoveries

Tessa B. Johung and Michelle Monje, Departments of Neurology, Neurosurgery and Pediatrics, Stanford University School of Medicine.

Basic Facts &Epidemiology

Diffuse Intrinsic Pontine Glioma (DIPG)is a devastating, aggressive brain tumor of childhood. It arises in the pons, a region of the brainstem involved in critical body functions. Though brainstem tumors are extremely rare among adults, they comprise approximately 10-15% of all pediatric brain tumors. DIPG is the most common subtype of tumor in this anatomical region and the second most common malignant brain tumor of childhood, with an estimated 200-400 children affected each year in the United States.1

Unfortunately, despite decades of clinical trials, DIPG remains incurable.  A dearth of available DIPG tissue and faithful animal models for research has limited preclinical evidence-based trial design until recently.  In the absence of effective therapies, DIPG currently represents the leading cause of death from pediatric brain cancer overall. Its prognosis is bleak: median age at diagnosis is 6-7 years, with median survival of 9 months. 90% of children will die from the disease within 2 years of initial diagnosis, with less than 1% surviving after 5 years.2

Clinical Characteristics

Because DIPG progresses rapidly, children typically experience one month or lessof symptoms before they are diagnosed.2Symptoms worsen quickly and are related to the growing tumor causing compression or dysfunction of anatomic structures in and near the pons. Abnormal alignment of the eyes results from dysfunction of cranial nerve VI (abducens palsy) and may cause double vision (diplopia); this nearly always occurs as an initial sign and sensitive positive predictor of DIPG.3Facial weakness or asymmetry may also result from damage to cranial nerve VII. Arm and leg weakness, increased deep tendon reflexes, and upward Babinski sign on neurologic examination may result from damage to the long motor tracts traveling from the brain to the spinal cord, passing through the pons. Walking, coordination or speech problems (ataxia, dysmetria, dysarthria) indicate involvement of the cerebellum. Together, these three sets of cranial nerve, long tract and cerebellar signs are known as the “classic triad” of DIPG presentation, though many patients may not demonstrate such typical findings.4 In less than 10% of children, posterior growth of the tumor may block the flow of CSF and cause hydrocephalus, a condition of increased pressure within the brain that results in headache, nausea and fatigue.

Diagnosis

The diagnosis of DIPG is based on the clinical history and examination combined with findings on magnetic resonance imaging (MRI). Because DIPG grows in a diffusely infiltrative pattern, intermixing with healthy tissue, the margins of the tumor do not appear well-defined on MRI, like other types of brainstem tumors. DIPG characteristically involves a majority of the pons and does not enhance with MRI contrast agent. These findings on diagnostic imaging help to distinguish DIPG from other, less aggressive brainstem cancers.3

Surgical biopsy is not routinely obtained to confirm diagnosis in the United States. Undertaking the risks of the procedure is thought to be unwarranted, as neuroimaging is sufficient for diagnosis in typical cases of DIPG, and biopsy has no role in guiding therapeutic management at the present state of the field in 2014. The rarity of DIPG biopsies has contributed to the scarcity of tumor tissue available for experimental study. In France, however, biopsies are now routinely performed for DIPG.4Currently, international and multi-institutional efforts to share tumor tissue and resources resulting from these biopsies, as well as from a growing pool of early post-mortem autopsy tissue donations by patients and their families, have resulted in expanded possibilities to study the disease. This has given way to a better understanding of its biology in recent years. As researchers begin to learn more about DIPG molecular and genetic markers and how they may be associated with disease trajectory and prognosis, some now speculate that eventual development of disease stratification and targeted therapies may warrant revisiting the role of biopsy for DIPG patients in the future.

Treatment

Because DIPG grows diffusely and infiltrates healthy tissue in the critical structures of the brainstem, surgical treatment is not possible.  Radiation therapy has remained the mainstay of treatment for DIPG for the past three decades. At most treatment centers, the standard recommendation is conventionally fractionated local field radiotherapy with dose range of 54-60 Gy for a period of 6 weeks.5Radiotherapyprovides temporary improvement or stabilization of symptoms and extends overall survival by an average of 3 months; median survival is less than 5 months with no radiation treatment.6Hyperfractionated therapy (smaller, more frequent doses) did not improve survival in multiple prior studies and was associated with increased side effects.7-10Newer studies suggest that hypofractionated therapy (larger doses over a shorter period of 3 weeks) may offer comparable overall survival with reduced burden on the patient and family, who were able to spend an average of less than 10% of remaining survival time in the hospital receiving treatment.11-12

Many clinical trials over the years have explored the use of various chemotherapeutic agents for DIPG, employing conventional and high-dose strategies as well as targeted agents. Chemotherapy has been attempted at time points before, during and after radiation therapy. Despite all efforts, no improvement in survival has been demonstrated.13-18Historically, these trials were performed largely without guidance by preclinical experimental data, and were instead designed after therapeutic strategies used to treat adult high-grade glioma. Such a strategy is likely to be problematic, as emerging research suggests DIPG represents a distinct disease from its adult counterpart. Newer, ongoing efforts by the DIPG Preclinical Consortium, formed in 2011 as an international collaboration of DIPG researchers, will attempt to harness the emerging availability of DIPG cell lines and animal models to ascertain efficacy of potential drugs at the preclinical level, directing future clinical trials.19

The extent to which the failure of previous clinical trials is due to inherent resistance of the tumor cells is unclear.  Drug delivery to the pons, where DIPG is located, likely also poses a major therapeutic challenge. Because of the blood-brain barrier that naturally protects the brain and regulates its environment, drugs intended to treat DIPG often do not effectively reach their target. Convection Enhanced Delivery (CED) may be a promising approach to bypass the blood-brain barrier and provide localized drug delivery in higher concentrations without systemic side effects. A catheter is placed into the region of the tumor by stereotactic surgery, and an attached pump locally delivers the drug under positive pressure.20In a recent clinical trial, CED was recently demonstrated to feasibly deliver the drug topotecan to the brainstems of children with DIPG; however, this trial highlighted the need for further technical optimization.21A phase I safety trial of CED, designed to optimize technical parameters, is ongoing (clinicaltrials.gov ID NCT01502917). CED continues to gain attention as a promising area of development in the treatment of DIPG.

Pathophysiology

In recent years, a rapid expansion in our understanding of the biology of DIPG has occurred alongside the expansion of available autopsy/biopsy tissue and animal models for molecular and genetic analysis. New research shows that most (~80%) DIPG tumors contain a specific, recurrent mutation in one of two genes encoding histones, structural proteins around which DNA is wound, which play important roles in the broad regulation of expression of sets of genes. The gene H3F3A encodes histone variant H3.3, whereas HIST1H3B encodes the variant H3.1; a specific mutation in either gene, referred to as the K27M mutation, results in a particular amino acid substitution in the histone, which alters its interaction with transcription modifiers.22-24 This in turn initiates broad changes in the gene expression (epigenetic) landscape. Such changes are thought to ultimately lead to tumor formation by switching on a pattern of gene expression similar to an expression pattern ofthe developing forebrain, where stem cell maintenance and self-renewal are key.25Resulting changes in the epigenetic landscape and gene expression, such as global inhibition of the Polycomb Repressive Complex 2 (PRC2)necessary for Histone 3 lysine 27 trimethylation and up-regulation of the oncogene MYCN, may underlie the development of the tumor, although the cellular and molecular context in which the H3K27M mutation results in tumor formation is not yet clear.26Elucidating these mechanisms is a current focus of intense research, with the goal of identifying additional therapeutic target candidates.

Other research continues to distinguish unique characteristics of DIPG. Although DIPG shares some histologic features with high-grade gliomas in adults, further research has suggested that it is a related but biologically discrete disease, with distinctive changes in genes and gene expression that contribute to the development of the tumor. DIPG, unlike adult disease, tends to exhibit gain of chromosome arm 1q and amplification of the gene PDGFRA that encodes alpha-type platelet-derived growth factor receptor, an important growth signaling molecule.27The fact that different genetic changes were implicated in the pediatric disease suggests that the brain of a child represents a distinct microenvironment that is uniquely susceptible to certain types of dysregulated cell signaling during development, resulting in transformation of healthy cells into malignant cancer cells.

The anatomic location of DIPG in the ventral pons likely represents another feature of the tumor micro environment that uniquely gives rise to the disease.  Researchers have found patterns of gene expression in DIPG (e.g. Hox and HLH over-expression) not shared with tumors arising in other areas.28Additionally, a stem cell-like population of cells found specifically in the human pons has been proposed as the initiating cell of DIPG. These pontine precursor cells, which mostly go on to become myelinating oligodendroglial cells in the mature brain, appear in the developing brain in the very region of the pons where DIPG arises; moreover, these cells peak in number during middle childhood, at the age of highest DIPG incidence.29 It is proposed that these unique cells may undergo malignant transformation into cancerous DIPG cells in response to aberrant signaling caused by changes in gene expression caused, in turn, by the H3K27M mutation.

Further discoveries are now suggestive of the existence of subgroups within DIPG, which may someday allow us to stratify the disease for prognostic and therapeutic purposes. Drawing subtype nomenclature from the adult GBM literature, an “oligodendroglial subtype” is thought to arise due to the PDGFRA gene amplification associated with some cases of DIPG; it appears to be the most clinically aggressive and resistant to radiotherapy.28This amplification is uniquely associated with the K27M mutation in H3.3.23A second, “mesenchymal/proangiogenic” subtype seems to be associated with a transition of glial cell behavior towards a more stem-cell-like pattern and is thought to be primarily driven by epigenetic changes. Ongoing efforts to understand the unique biology of DIPG will be critical in the development of novel targeted therapies to more effectively fight this disease.

Summary

DIPG is an aggressive and lethal type of brain cancer affecting hundreds of children each year in the US alone. It intermixes with healthy tissue in the pons, a region of the brainstem containing many critical structures for basic body functions, and causes progressive neurologic symptoms involving control and coordination of the face and body. Due to its location and diffuse growth pattern, it cannot be surgically removed. Radiation therapy is the standard treatment, but results in just a few months of temporary stabilization of symptoms. Improved availability of tumor tissue for preclinical investigation, alongside the development of experimental model systems, now provides important tools to guide future clinical trials. Until recently, the biology of DIPG was poorly understood, but new advances in our understanding of the broad gene expression changes driving DIPG development show new promise for developing novel effective therapies to treat this devastating disease.

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