**1. Introduction**

Diffuse intrinsic pontine glioma (DIPG) is a tumor that arises in the pons and diffusely infiltrates the brainstem. It is believed that DIPG originates from a dysregulation of a postnatal

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neurodevelopmental process. It usually affects middle childhood, with a peak onset of 6–9 years of age. High-grade gliomas (HGGs) typically have a predilection for the ventral pons, a finding that would reflect the presence of a cell of origin as well as a signaling microenviron‐ ment favorable for tumor formation [1–3]. A study using early postmortem DIPG tumor tissue has shown that the Sonic Hedgehog (Shh) signaling pathway in DIPG tumor cells is in‐ volved in many developmental and oncogenic processes, such as neural embryogenesis and oligodendrogenesis. The dysregulation of this molecular system in DIPG leads to hypertro‐ phy of the ventral pons and suggests a potential molecular origin for this poorly understood cancer [4]. According to the lessons learned from other pediatric brain tumors, such as medulloblastoma, neural stem or precursor cells would be the most likely cell type that could transform and give rise to DIPG [4–6].

In the United States, 200–300 children are diagnosed each year with DIPG [7]. Unfortunately, being the pediatric brain tumor with the highest mortality rate, DIPGs have poor prognosis with a less than 1-year survival, where less than 10% and 2% of patients survive after 2 and 5 years post-diagnosis, respectively [8]. The grim outcome first and foremost is due to the tumor's delicate anatomical location and significant infiltration. Extensive surgical resection is not a treatment option, leaving radiation therapy (RT) and chemotherapy as the only remaining therapies.

RT is the standard treatment for children with DIPG and results in improvement of symp‐ toms in more than 80% of the patients; however, it rarely results in a cure. The conventional treatment consists of 1.8 Gy fractions delivered once daily, 5 days a week, for about 6 weeks to a total cumulative target dose of 54 Gy. Hyperfractionated doses up to 72 Gy have not shown improved efficacy in children and resulted in increased morbidity. On the other hand, hypofractionated RT may lead to similar outcomes as standard treatment. The median survival of patients treated with RT is only 10 months [9,10]. When RT is associated with standard chemotherapeutic agents, no survival benefit was shown, in neither the event-free survival (EFS) nor the overall survival (OS) of patients [11].

Another reason of poor prognosis is associated with the ineffective results using chemother‐ apeutic agents. Despite decades of research and use of different chemotherapeutic strategies, no survival advantage has been achieved. In the last 30 years, several clinical trials were done using various adjuvant chemotherapeutic drugs utilized prior to, during, or after radiothera‐ py in DIPG patients. The results were bleak: none of these clinical trials showed any improve‐ ment in survival of this pediatric cancer, leaving DIPG as the number one cause of brain tumorrelated death in children [12]. In addition to the difficulty associated with finding effective therapeutics, it is also speculated that the tumor biology changes between the primary and recurrent tumors, leading to another problem—resistance to therapy. Furthermore, an additional challenge includes ways of overcoming the restrictive ability of the intact blood– brain barrier (BBB) in patients with DIPG.

The lack of reliable models along with poor knowledge of the biological basis of DIPG has been critical elements in failure to make progress in this disease. In the pre-CT and magnetic resonance imaging (MRI) eras, histological assessment of biopsies was routinely conducted to diagnose DIPGs. However, this standard of care was discontinued in the early 1990s, due to

the high rate of morbidity and improvement of imaging techniques [13]. Recently, the increase in availability for biopsy and acquisition of autopsy specimen for experimental purposes, as well as the insight gleaned from recent studies, is beginning to unravel the genetic and epigenetic drivers of DIPG. Stereotactic biopsies in well-trained neurosurgical teams are a safe procedure [14] and are being incorporated for patients with DIPG. Improved methods of modeling DIPGs by mimicking genetic and epigenetic changes, preclinical testing, and translational studies will bring a strong incentive to move new treatments forward into clinical trials.

Given the different molecular subgroups within the disease and the combinatory mutations found through gene expression, mutational, and epigenetic analysis, the key for an effective treatment relies on combinatory therapy. Studies using deep sequencing analysis, compre‐ hensive methylation, copy number, and mRNA expression profiling show that these sub‐ groups are characterized by upregulation of MYCN (N-Myc), Shh signaling, and H3-K27M mutations [15–18]. The combinatory genomic aberrations have introduced one more chal‐ lenge for designing therapeutic regiments—most of the combinatory mutations are novel and thus there is a deficit of preclinical data on combinatory drug regimens. However, the increase in knowledge of DIPG and development of novel *in vitro* and *in vivo* approaches is a prom‐ ise for effectively targeting driver mutations with the use of combinatory drugs.

New promising approaches provide a glimpse of hope for patients who are battling this devastating tumor. Among the many devastating childhood cancers, DIPG patients desper‐ ately need access to new treatments. Increased availability of tumor tissue for preclinical investigation and the development of experimental model systems now provide important tools to guide future clinical trials. Advances in the knowledge of the molecular biology of DIPG are key to developing new therapeutic testing.
