Review
Developing chemotherapy for diffuse pontine intrinsic gliomas (DIPG)

https://doi.org/10.1016/j.critrevonc.2017.10.013Get rights and content

Highlights

  • New WHO glioma classification of diffuse midline glioma with H3 K27M mutation calls for a biopsy of diffuse intrinsic pontine glioma (DIPG).

  • Biological characteristics of DIPG are different from supratentorial high grade glioma.

  • Monoclonal antibodies and target inhibitors are on-going clinical trials.

  • Spontaneous DIPG animal model using RCAS/tv-a seems to be promising.

  • Recent advancement of convection enhanced delivery technique could solve drug delivery problem in DIPG.

Abstract

Prognosis of diffuse intrinsic pontine glioma (DIPG) is poor, with a median survival of 10 months after radiation. At present, chemotherapy has failed to show benefits over radiation.

Advances in biotechnology have enabled the use of autopsy specimens for genomic analyses and molecular profiling of DIPG, which are quite different from those of supratentorial high grade glioma. Recently, combined treatments of cytotoxic agents with target inhibitors, based on biopsied tissue, are being examined in on-going trials. Spontaneous DIPG mice models have been recently developed that is useful for preclinical studies. Finally, the convection-enhanced delivery could be used to infuse drugs directly into the brainstem parenchyma, to which conventional systemic administration fails to achieve effective concentration.

The WHO glioma classification defines a diffuse midline glioma with a H3-K27M-mutation, and we expect increase of tissue confirmation of DIPG, which will give us the biological information helping the development of a targeted therapy.

Introduction

Brainstem gliomas (BSG) account for 15–20% of all childhood central nervous system (CNS) tumors (Stiller and Nectoux, 1994), and up to 85% of these cases are diffuse intrinsic pontine gliomas (DIPG) (Hargrave et al., 2006). At present, DIPG represents the biggest therapeutic challenge of all BSG subtypes. In addition to occupying critical pathways and nuclei, DIPG has a diffuse, infiltrative nature that has given it a reputation of being ‘untouchable’. Radiation is the standard treatment for DIPG; however, despite collaborative efforts to improve treatments, the survival rate of patients with DIPG has remained static over the last 20 years: median survival is about 10 months and the two-year survival rate is less than 10% (Hargrave et al., 2006).

Treatment of DIPG with chemotherapy has failed to show benefits beyond traditional radiation therapy over the past decades, which could be due to a number of reasons (Frazier et al., 2009, Hargrave et al., 2006, Jansen et al., 2012). Most notably, the majority of these clinical trials used chemotherapy regimens or therapeutic strategies similar to that of cerebral high grade glioma (HGG), based on the incorrect assumption that the biologic properties of DIPG are identical to HGG. While chemotherapeutic agents have achieved some success traversing the blood brain barrier (BBB) to reach HGG, the more compact texture of the brainstem is a major limit of BBB permeability for the drug to reach DIPG (Vanan and Eisenstat, 2015). Furthermore, the non-enhancing nature of these tumors further decreases the likelihood of chemotherapeutic agents being delivered through the blood-tumor-barrier, through which enhancing cerebral gliomas allow the penetration of contrast agents (Groothuis, 2000). Neurosurgical attempts have been made at circumventing the BBB to deliver drugs directly into the brainstem parenchyma, using the convection-enhanced delivery (CED) technique (Asthagiri et al., 2011, Lonser et al., 2007). In CED, volume of distribution (Vd) increased inversely proportional to the interstitial space. Thus, compact texture of brainstem contributes to increase of drug distribution in CED (Song and Lonser, 2008).

Another challenge of DIPG is that the sensitive location of these tumors makes it too difficult to obtain tissues for diagnosis. The resulting lack in surgical specimens has hindered our understanding of the biology of these tumors and the development of targeted therapy. Recent studies demonstrated that autopsied tissue samples taken from children with DIPG can provide DNA and RNA of high enough quality to conduct genome-wide single nucleotide polymorphism (SNP) arrays (Broniscer et al., 2010a, Li et al., 2012, Warren et al., 2012). Comprehensive high-resolution genomic analyses and integrated molecular profiling of tissue samples have revealed therapeutic molecular targets for treating these tumors, such as platelet-derived growth factor receptor-α (PDGFRA) and poly ADP-ribose polymerase (PARP)-1 (Grill et al., 2012, Puget et al., 2012, Zarghooni et al., 2010). Additionally, the first genetically engineered PDGF-induced spontaneous BSG model, using the RCAS/tv-a system, can serve as a preclinical tool for the testing of novel agents (Becher et al., 2010).

Current and proposed clinical studies are combining radiation therapy and/or chemotherapy with new agents that have shown promise in biological and preclinical studies, such as anti-angiogenic agents, growth factor receptor inhibitors, histone deacetylase (HDAC) inhibitors, and immunotherapy (Jansen et al., 2012; Massimino et al., 2011). New and innovative strategies continue to be explored to improve the prognosis of these fatal diseases.

Section snippets

Difficulties of performing prospective trials

The annual incidence of DIPG is less than one in a million, as only 100–150 children develop these tumors every year in the USA (Smith et al., 1998). Thus, despite collaborative efforts, the design of prospective trials for this rare disease is hindered by regional and time limitations. Additionally, there is an uncertainty in the diagnosis of DIPG which, without access to biopsied tissues, has been mostly dependent on radiological findings and has been characterized by different clinical

Is the tissue biopsy of DIPG both necessary and feasible?

Following the consecutive failures of chemotherapy, which is effective in supratentorial HGG, it was suspected that the biological characteristics of DIPG may be different from those of HGG. However, the necessity of a histological confirmation of DIPG has been questioned given the possible morbidity of a penetrating critical structure, as well as the fact that confirming a diagnosis of DIPG will not change the treatment course or outcomes (Albright et al., 1993). Conversely, it has been

Small molecular weight target inhibitors

Since cytotoxic chemotherapies have continued to be ineffective against DIPG, the use of targeted agents has been explored as an alternative to conventional chemotherapy (Broniscer et al., 2010b, Pollack et al., 2011). Most trials investigating targeted inhibitors in DIPG cases have been early (phase 1 or 2) and were performed along with other brain tumors or solid cancers (Table 1). Among the included target inhibitors, imatinib (Gleevec®) has shown promise by inhibiting the PDGF/PDGFR

Technical aspects of CED for DIPG

Reduced permability of brainstem BBB compared to cerebral cortex is a major obstacle for the chemotherapeutic agent reaching DIPG (Vanan and Eisenstat, 2015). Both compact texture of brainstem and the lack of fenestrated tumor capillary (non-enhancing nature) in DIPG have been considered to contribute to the reduced BBB permeability (Groothuis, 2000, Song and Lonser, 2008). Recently, Subashi et al. proved that not biological property of H3.3K27M mutation but tumor location (cereberal cortex vs.

Advanced animal models for DIPG

As mentioned previously, the biological character of DIPG is different from that of supratentorial HGG, representative animal models are critical for preclinical studies for DIPG. As a result, the orthotopic xenograft model, in which supratentorial HGG cells are stereotactically introduced to the pons, does not reflect all the biological characteristics of DIPG, although it has been shown to have a typical infiltrating pattern (Caretti et al., 2011, Jallo et al., 2006). Monje et al.

Future directions and the recently updated classification of diffuse midline glioma

In a recent update to the WHO classification of gliomas, a ‘diffuse midline glioma, H3 K27M–mutant’ has been newly defined and now includes tumors previously referred to as DIPG (Khuong-Quang et al., 2012; Louis et al., 2016). The delineation of this clinical disease entity into a phenotypically and molecularly defined set of tumors calls for the development of targeted therapies that overcome the effects of these mutations. After it is known that reduced H3K2me3 and DNA hypomethylation are

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Funding

This work was supported by a grant from the National Cancer Center, Korea (NCC-1511000-3 and NCC-1710871-1), and the Ministry of Health and Welfare, Research Fund (1731340-1).

Ho-Shin Gwak, M.D., PhD.: Current position: Neurosurgeon, Neuro-Oncology clinic, National Cancer Center/Professor, Department of System Cancer Science, National Cancer Center Graduate School of Cancer Science and Policy. Organization: Korean Neurosurgical Society (1995-present). Korean Brain Tumor Society (1998-present). Korean Skull Base Society (2001-present). Society for Neuro-Oncology (2007-present). Korean Society for Neuro-Oncology (2011-present). Education: College of Medicine, Seoul

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    Ho-Shin Gwak, M.D., PhD.: Current position: Neurosurgeon, Neuro-Oncology clinic, National Cancer Center/Professor, Department of System Cancer Science, National Cancer Center Graduate School of Cancer Science and Policy. Organization: Korean Neurosurgical Society (1995-present). Korean Brain Tumor Society (1998-present). Korean Skull Base Society (2001-present). Society for Neuro-Oncology (2007-present). Korean Society for Neuro-Oncology (2011-present). Education: College of Medicine, Seoul National University. M.D., 1986–1990, − Graduated School of Medicine, Seoul National University, Ph.D. (1999- 2004), Neurosurgery. Post-graduate training: Internship & Residency: 1990–1995, Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. Fellowship: 1998–2000 Neurosurgery (Brain tumor & GammaKnife radiosurgery), Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. Postdoctoral Fellow, 2006–2007, Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. Postdoctoral Fellow, 2007–2008, Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA. Professional Experiences: Staff Neurosurgeon (full time), Department of Neurosurgery, Korean Institute of Radiological and Medical Science, 2000–2006. Neurosurgeon, Neuro-Oncology clinic, National Cancer Center, Korea (2008-present). Professor, Department of System Cancer Science, Graduate School of Cancer Science and Policy (2015-present). Awards: 2013 The highest academic article, clinical field, 53th Annual meeting of Korean Neurological Society, (Single-stage posterior decompression and stabilization for metastasis of the thoracic spine: Prognostic factors for functional outcome and patient’s survival. The Spine Journal). 2014 The best academic article award, clinical, 24th Annual meeting of Korean Brain Tumor Society, (Ventriculo-lumbar perfusion chemotherapy for the treatment of leptomeningeal carcinomatosis: a phase 1 study with pharmacokinetic data. American Journal of Clinical Oncology). 2016 The best academic article, basic research field, 8th Annual meeting of Korean Cancer Association, (Radiation-induced autophagy contributes to cell death and induces apoptosis partly in malignant glioma cells). Major Interest: Surgery of Brain tumor, Neuro-Oncology (brain metastasis, CSF dissemination of cancer), Radiation biology.

    Hyeon Jin Park, M.D., PhD.: Current position: Pediatrician, Center for Pediatric Cancer, National Cancer Center. Organization: Korean Society for Pediatric Neuro-oncology (2002-present). Korean Soceity for Hematology (2008-present). Korean Soceity of Blood and Marrow Transplantation (2007-present). Korean Soceity for Pediatric-Hematology-Oncology (2011-present). Korean Society for Neuro-Oncology (2011-present). Education: College of Medicine, Seoul National University. M.D., 1987–1991, − Graduated School of Medicine, Seoul National University, Ph.D. (1998- 2004), Pediatrics. Post-graduate training: Internship & Residency: 1991–1996, Department of Pediatrics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. Fellowship: 1996 Pediatrics (Pediatric Oncology & Hematology), Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. Postdoctoral Fellow, 1999–2001, Department of Pediatrics, Medical college of Georgia, Augusta, GA, USA. Professional Experiences: Staff Pediatrician (full time), Department of Pediatrics, Chungbuk National University College of Medicine, 1999–2005. Pediatrician, Center for Pediatric Cancer, National Cancer Center, Korea (2005-present). Major Interest: Pediatric Brain tumor, Leukemia, Bone marrow transplantation.

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