Advancements in Epigenomics and Immunotherapeutic in Pediatric Brain Tumors

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Paediatric brain tumours are a heterogeneous group of tumours with remarkable differences in treatment outcomes. With the help of molecular profiling, it has now been shown that paediatric brain tumours are significantly different from adult brain tumours despite sharing similar histology. Moreover, treatments that are generally well-tolerated by the adult brain (i.e. radiation therapy) may have negative effects on the normal development of paediatric patients. The differences in treatment response for brain tumours can now be partly explained based on the heterogeneous molecular/gene expression profiles. The WHO has therefore modified the consensus definitions of brain tumours in the year 2016 to include genotypic characteristics of tumours along with the previously used phenotypical parameters . In this paper, we review the advancements in the characterisation, molecular profiling and development of novel epigenetic, and immunotherapeutic options available or under investigation for the treatment of paediatric brain tumours. The limitations and drawbacks of these innovative technologies in addressing the unmet clinical need in the treatment of paediatric tumours are also explored.
The most common paediatric tumours include the high-grade gliomas, medulloblastomas, low-grade gliomas, ependymomas, and brainstem gliomas/diffuse intrinsic pontine gliomas (DIPGs). High-grade gliomas (HGGs) are malignant, infiltrating astrocytic tumours of WHO grade III (anaplastic astrocytoma) and grade IV (glioma). Paediatric (pHGGs) are also biologically distinct from adult HGGs with a higher frequency of PDGF/PDGFR genomic alterations and mutations in the histone H3.3 gene and a lower frequency of PTEN and EGFR genomic alterations, which have been used in the classification of pediatric tumors .
As is evident from years of clinical experience, the success of surgery, radiotherapy, and chemotherapy alone or in combination against aggressive brain tumours has been limited, calling for research into novel molecular mechanisms that could be used as potential therapeutic targets. Epigenetic mechanisms such as DNA methylation and acetylation regulate gene expression in a reversible manner without changing the original DNA sequence. The identification of signalling mechanisms that regulate epigenetic changes has produced novel targets for cancer treatments, particularly treatments for CNS tumours. Moreover they are excellent targets for the purpose of tumour classification and development of diagnostic tools. Since tumours have altered patterns of epigenetic modifications compared to healthy tissues and tumour cells may also acquire epigenetic alterations to escape chemotherapy i.e. as a survival response against chemotherapy and host immune surveillance. Profiling DNA methylation pattern of brain tumours has been used as an important tool to exclude less malignant tumours that could otherwise be misdiagnosed on the basis of histological features. Since a large proportion of paediatric tumours lack genetic lesions or specific drivers detected by Next generation sequencing (NGS), epigenetic changes in paediatric CNS tumours may serve as therapeutic drug targets. As tumours originating in infants, young children, and adolescents have different epigenetic profiles, it has now been possible to classify paediatric ependyomas to include three new molecular classes consisting of supratentorial YAP1‐fusion‐positive ependymomas, a benign spinal ependymoma and a class closely related to the histological group of myxopapillary ependymoma . These new classifications have also revealed higher rates of misdiagnosis when using histopathological classification alone. Advancements in the epigenetic classification of paediatric tumours can be a valuable tool in clinical decision making for selection of most appropriate treatment options when used in combination with histological classification. Several types of brain tumors are vulnerable to treatment with Histone deacetylase inhibitors (HDACis) and a number of HDACis have been tested in clinical trials. DNA methyltransferase (DNMT) inhibitors azacytidine and decitabine are highly effective epigenetic drugs which have been evaluated for safety and efficacy in a number of paediatric brain tumors. However, the use of epigenetics to develop treatment options is not without a cache. One of the key challenges in targeting epigenetic mechanisms in the development of therapeutics against paediatric use include the ubiquity of the HDAC enzymes and their role in other cellular mechanisms, which may be disrupted upon blanket targeting of the HDACs.
Immunotherapy uses the body’s own immune mechanisms to target the tumours. High mutational burden, high prevalence of tumour neoantigens, and a higher frequency of mutations in repair pathways have been associated with a favourable response to immune checkpoint inhibitors. Paediatric brain tumors remain a formidable challenge for the development of immunotherapeutics due to their low mutational burden, location in a unique tumour microenvironment which is protected by the blood-brain barrier, and intratumoral heterogeneity. Barriers to overcome the use of immunotherapy for pediatric brain tumours include optimization of delivery techniques for adequate penetration of the therapeutic across the blood-brain barrier as well as the exposure of poorly perfused areas of the tumors to the novel therapeutics. Combinatorial approach targeting multiple tumour specific antigens, as well as combined checkpoint blockade with immunotherapeutics will enable penetration of the therapeutic agent into the highly immunosuppressive tumour microenvironment. Clinical trials on immune checkpoint inhibitors for pediatric brain cancers are expected to have a greater impact if patients with and without high mutational burdens are included in the trials to decipher the populations that are most likely to benefit from the treatment. In general, as clinical trials on immune checkpoint inhibitors are conducted on patients treated with combination therapies, it is difficult to assess the disease response to novel therapies. CAR-T cell therapy targeting tumour-specific antigens provides a personalised therapy to initiate an active immune reaction against the tumour. It may therefore be useful against paediatric brain tumours with a low mutational load.
It is expected that genetic profiling will provide a robust and accurate molecular characterization system (Fig. 1). Integrating these robust profiling techniques in the diagnosis and management of pediatric brain tumors is expected to complement standard therapies in clinical decision making for pediatric brain tumour patients while also assisting in improving future clinical trial designs, especially in patient profiling for recruitment in clinical trials. 


 
Figure 1. Systematic approach integrating molecular diagnostics in clinical decision making and therapeutic management of paediatric tumours.

Epigenetics and immunotherapy have opened previously unchartered territories in targeting paediatric brain tumors but these novel therapeutics remain to be extensively validated in real-world settings. Options such as oncolytic virus therapy, which bypass the need for neoantigens, are promising, particularly when included in combination approaches. While modulation of immune inhibitory pathways presents a significant breakthrough in cancer clinical trials, these techniques often require a personalized approach towards treatment depending on the molecular profile of the tumors. We have many new avenues to explore which include immune checkpoint blockade pathways, epigenetic modulators, such as histone deacetylase inhibitors (HDACis) or DNA methyltransferases (DNMTi), immunotherapy with CAR-T cells, and oncolytic viruses which need to substantiated for efficacy and safety in a real-world settings. 

References

[1] The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131, 803-820 (2016).

[2] Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520-537.e5 (2017)

[3] Molecular characterization of histopathological ependymoma variants. Acta Neuropathol. 139, 305-318 (2020).

Malak S Abedalthagafi

Director , KACST/KFMC

Genomics, RDI, pathology, women in STEMM, cancer