World Cancer Day 2021 - Perspectives in Pediatric and Adult Neuro-Oncology

Sulman, Erik P.; Eisenstat, David D.

doi:10.3389/fonc.2021.659800

“…12,13 The standard of care treatment for DMG remains palliative radiotherapy which extends survival by only months for those that respond. 14 In addition to radiation, the immunosuppressant corticosteroid, dexamethasone is almost always administered to decrease the neurological symptoms associated with peritumoral edema. Hence, there is a clear priority to develop new treatment strategies for children and young adults diagnosed with DMG.…”

Section: Neuro-oncologymentioning

confidence: 99%

The intrinsic and microenvironmental features of diffuse midline glioma: Implications for the development of effective immunotherapeutic treatment strategies

Persson

¹

,

Douglas

²

,

Alvaro

³

et al. 2022

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Diffuse midline glioma (DMG), including those of the brainstem (diffuse intrinsic pontine glioma), are pediatric tumors of the central nervous system (CNS). Recognized as the most lethal of all childhood cancers, palliative radiotherapy remains the only proven treatment option, however, even for those that respond, survival is only temporarily extended. DMG harbor an immunologically “cold” tumor microenvironment (TME) with few infiltrating immune cells. The mechanisms underpinning the cold TME are not well understood. Low expression levels of immune checkpoint proteins, including PD-1, PD-L1, and CTLA-4, are recurring features of DMG and likely contribute to the lack of response to immune checkpoint inhibitors (ICIs). The unique epigenetic signatures (including stem cell-like methylation patterns), a low tumor mutational burden, and recurring somatic mutations (H3K27M, TP53, ACVR1, MYC, and PIK3CA), possibly play a role in the reduced efficacy of traditional immunotherapies. Therefore, to circumvent the lack of efficacy thus far seen for the use of ICIs, adoptive cell transfer (including chimeric antigen receptor T cells) and the use of oncolytic viruses, are currently being evaluated for the treatment of DMG. It remains an absolute imperative that we improve our understanding of DMG’s intrinsic and TME features if patients are to realize the potential benefits offered by these sophisticated treatments. Herein, we summarize the limitations of immunotherapeutic approaches, highlight the emerging safety and clinical efficacy shown for sophisticated cell-based therapies, as well as the evolving knowledge underpinning the DMG-immune axis, to guide the development of immunotherapies that we hope will improve outcomes.

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“…Clinical management of pDMG and especially of DIPG is a major challenge given their location in vital nervous centers and their leptomeningeal dissemination, which prevent any prospect of surgical intervention 6 . Radiotherapy, the current standard-of-care, is at best only transiently effective 3,7 .…”

Section: Introductionmentioning

confidence: 99%

“…Clinical management of pDMG and especially of DIPG is a major challenge given their location in vital nervous centers and their leptomeningeal dissemination, which prevent any prospect of surgical intervention 6 . Radiotherapy, the current standard-of-care, is at best only transiently effective 3,7 . Moreover, pDMG are highly resistant to currently available chemotherapies although promising combinations of molecules, including ONC201, are currently in clinical trials 8 .…”

Section: Introductionmentioning

confidence: 99%

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

Huchedé,

Meyer,

Berthelot

et al. 2023

Preprint

0

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Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the BMP/K27M crosstalk.

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“…Pediatric Diffuse Midline Gliomas (pDMG), including Diffuse Intrinsic Pontine Gliomas (DIPG) are rare and aggressive brain tumors that arise in the pons, thalamus or spinal cord of children, most commonly between the ages of 5 and 10 1-3 . pDMG are almost uniformly fatal, with a median overall survival of 9 to 11 months 4,5 , thereby representing the leading cause of mortality in pediatric neuro-oncology 1,3 .…”

Section: Introductionmentioning

confidence: 99%

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

Huchedé,

Meyer,

Berthelot

et al. 2023

Preprint

0

View full text Add to dashboard Cite

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the BMP/K27M crosstalk.

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World Cancer Day 2021 - Perspectives in Pediatric and Adult Neuro-Oncology

Cited by 9 publications

References 109 publications

The intrinsic and microenvironmental features of diffuse midline glioma: Implications for the development of effective immunotherapeutic treatment strategies

The intrinsic and microenvironmental features of diffuse midline glioma: Implications for the development of effective immunotherapeutic treatment strategies

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

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