Cancers (Basel). 2024 Mar 30;16(7):1361. doi: 10.3390/cancers16071361.

ABSTRACT

Pediatric cancers are the leading cause of disease-related deaths in children and adolescents. Most of these tumors are difficult to treat and have poor overall survival. Concerns have also been raised about drug toxicity and long-term detrimental side effects of therapies. In this review, we discuss the advantages and unique attributes of zebrafish as pediatric cancer models and their importance in targeted drug discovery and toxicity assays. We have also placed a special focus on zebrafish models of pediatric brain cancers-the most common and difficult solid tumor to treat.

PMID:38611039 | PMC:PMC11010887 | DOI:10.3390/cancers16071361

Cancer Lett. 2024 Apr 10;590:216876. doi: 10.1016/j.canlet.2024.216876. Online ahead of print.

ABSTRACT

Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.

PMID:38609002 | DOI:10.1016/j.canlet.2024.216876

J Pediatr Hematol Oncol. 2024 May 1;46(4):211-215. doi: 10.1097/MPH.0000000000002853. Epub 2024 Apr 4.

ABSTRACT

Diffuse intrinsic pontine gliomas are lethal tumors with a prognosis generally less than 1 year. Few cases of survivors of 5 years or more have been reported. This case report highlights the journey of a 9.5-year survivor who underwent 3 rounds of focal radiotherapy; she experienced 6 years of progression-free survival following the first round but ultimately succumbed to her disease. An autopsy revealed a favorable IDH1 mutation and the absence of H3K27M. This case reiterates the importance of extensive molecular analyses in diffuse intrinsic pontine gliomas and explores the potential benefit of re-irradiation in patients with positive responses and long periods of remission.

PMID:38573000 | DOI:10.1097/MPH.0000000000002853

Neuro Oncol. 2024 Mar 30:noae066. doi: 10.1093/neuonc/noae066. Online ahead of print.

ABSTRACT

BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.

METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq and multiplexed immunofluorescence staining.

RESULTS: The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype.

CONCLUSIONS: The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.

PMID:38554031 | DOI:10.1093/neuonc/noae066

Neurooncol Adv. 2024 Mar 16;6(1):vdae029. doi: 10.1093/noajnl/vdae029. eCollection 2024 Jan-Dec.

ABSTRACT

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) pose a significant challenge as a highly aggressive and currently incurable form of pediatric brain cancer, necessitating the development of novel therapeutic strategies. Omacetaxine, an FDA-approved protein synthesis inhibitor for treating certain hematological malignancies, was investigated for its potential antitumor effects against preclinical DIPG models.

METHODS: We employed primary DIPG cultures to study omacetaxine's cytotoxicity and its impact on colony formation. Annexin V staining and flow cytometry assessed apoptosis. Wound healing assays evaluated migration, while western blotting determined inhibition of oncogenic proteins. We tested omacetaxine's therapeutic efficacy in an orthotopic DIPG model and assessed brain penetration using mass spectrometry.

RESULTS: We found a pronounced cytotoxic activity of omacetaxine against DIPG neurospheres, with low IC₅₀ values of approximately 20 nM. Omacetaxine exerted its anti-proliferative effect by inhibiting protein synthesis and the induction of apoptotic pathways, evidenced by significant elevated levels of cleaved caspase 3 and cleaved PARP, both key markers of apoptosis. Omacetaxine effectively targeted oncogenic players such as PDGFRα and PI3K without additional effects on the mTOR signaling pathway. Furthermore, our study revealed the inhibitory effects of omacetaxine on cell migration, and a significant reduction in integrin/FAK signaling, which plays a crucial role in tumor progression and metastasis.

CONCLUSIONS: Despite these promising in vitro effects, omacetaxine's efficacy in an orthotopic DIPG model was limited due to inadequate penetration across the blood-brain barrier. As such, further research and advancements are crucial to improve the drug's brain penetration, thus enhancing its overall therapeutic potential.

PMID:38550394 | PMC:PMC10976909 | DOI:10.1093/noajnl/vdae029

Int J Mol Sci. 2024 Mar 15;25(6):3361. doi: 10.3390/ijms25063361.

ABSTRACT

The BMP pathway is one of the major signaling pathways in embryonic development, ontogeny and homeostasis, identified many years ago by pioneers in developmental biology. Evidence of the deregulation of its activity has also emerged in many cancers, with complex and sometimes opposing effects. Recently, its role has been suspected in Diffuse Midline Gliomas (DMG), among which Diffuse Intrinsic Pontine Gliomas (DIPG) are one of the most complex challenges in pediatric oncology. Genomic sequencing has led to understanding part of their molecular etiology, with the identification of histone H3 mutations in a large proportion of patients. The epigenetic remodeling associated with these genetic alterations has also been precisely described, creating a permissive context for oncogenic transcriptional program activation. This review aims to describe the new findings about the involvement of BMP pathway activation in these tumors, placing their appearance in a developmental context. Targeting the oncogenic synergy resulting from this pathway activation in an H3K27M context could offer new therapeutic perspectives based on targeting treatment-resistant cell states.

PMID:38542334 | PMC:PMC10969837 | DOI:10.3390/ijms25063361