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Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma.

ABSTRACT: Brain tumours are the leading cause of paediatric cancer-associated death worldwide. High-grade glioma (HGG) represents a main cause of paediatric brain tumours and is associated with poor prognosis despite surgical and chemoradiotherapeutic advances. The molecular genetics of paediatric HGG (pHGG) are distinct from those in adults, and therefore, adult clinical trial data cannot be extrapolated to children. Compared to adult HGG, pHGG is characterised by more frequent mutations in PDGFRA, TP53 and recurrent K27M and G34R/V mutations on histone H3. Ongoing trials are investigating novel targeted therapies in pHGG. Promising results have been achieved with BRAF/MEK and PI3K/mTOR inhibitors. Combination of PI3K/mTOR, EGFR, CDK4/6, and HDAC inhibitors are potentially viable options. Inhibitors targeting the UPS proteosome, ADAM10/17, IDO, and XPO1 are more novel and are being investigated in early-phase trials. Despite preclinical and clinical trials holding promise for the discovery of effective pHGG treatments, several issues persist. Inadequate blood-brain barrier penetration, unfavourable pharmacokinetics, dose-limiting toxicities, long-term adverse effects in the developing child, and short-lived duration of response due to relapse and resistance highlight the need for further improvement. Future pHGG management will largely depend on selecting combination therapies which work synergistically based on a sound knowledge of the underlying molecular target pathways. A systematic investigation of multimodal therapy with chemoradiotherapy, surgery, target agents and immunotherapy is paramount. This review provides a comprehensive overview of pHGG focusing on molecular genetics and novel targeted therapies. The diagnostics, genetic discrepancies with adults and their clinical implications, as well as conventional treatment approaches are discussed.

SUBMITTER: Rallis KS

PROVIDER: S-EPMC9247880 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.

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Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma.

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