Medulloblastoma

4 pts received TT at recurrence, within clinical trials: one with grade 3 meningioma and ALK rearrangement treated with alectinib, one with PTCH1 mutant medulloblastoma treated with vismodegib, and two with high TMB treated with nivolumab/ipilumumab. The incidence of targettable molecular alterations in adult CNS tumor patients was lower than in GBM. Nevertheless, in a few selected cases TT have the potential to increase treatment options at recurrence and improve outcomes.

A better diagnostic approach is to perform genetic testing to rule out the risk as early as possible when a newborn presents with cafe-au-lait spots, which are a typical feature of hereditary syndromes. Therefore, it is important to use germline genetic testing, combined with clinical phenotypic observation, to establish a diagnosis of a cancer susceptibility syndrome caused by an MMR gene mutation.

We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) Barasertib (AZD1152-HQPA) and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, and Grp3 MB...We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor Dasatinib acts synergistically to repress tumor growth and expansion in the highly invasive MB cell model ONS-76, but not in Grp3 MB cells...In conclusion, we demonstrate that AURKB is essential for MB tumor growth and expansion in the tissue context and the inhibition of AURKB is equally efficient as irradiation in repressing tumor cell growth. In patients younger than three years, pharmacological targeting of AURKB may thus constitute a novel means to overcome radiotherapy limitations.

The present study investigated cytokine profiles in the CSF of pediatric patients with MB. Our results suggest that these differentially expressed cytokines may serve as novel markers for detecting MB, especially for assessing the risk of progression and metastasis.

Further analysis of clinical serum samples revealed that B2S2PI was capable of accurately distinguishing MB patients from noncancer controls with an area under the curve (AUC) of 0.99, which was superior to that of qRT-PCR. B2S2PI holds promise as a novel alternative means for single-molecule miRNA assay and sheds light on the circulating nucleic acid-based liquid biopsy of intracranial malignant tumors.

P1/2, N=65, Recruiting, Nationwide Children's Hospital | Trial primary completion date: Nov 2025 --> Nov 2027

This review examined the research progress of chimeric antigen receptor T-cell therapy in gliomas, medulloblastomas, and lymphohematopoietic tumors of the central nervous system, focusing on chimeric antigen receptor T-cells targeting antigens such as EGFRvIII, HER2, B7H3, GD2, and CD19 in preclinical and clinical studies. It synthesized current research findings to offer valuable insights for future chimeric antigen receptor T-cell therapeutic strategies for central nervous system tumors and advance the development and application of this therapeutic modality in this domain.

P1, N=18, Recruiting, Emory University | Initiation date: Oct 2024 --> Jan 2025

P2, N=23, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

Therefore, the present review serves to underline the update on recent research pertaining to KMT2D gene, that could be a potential therapeutic target in downregulating glycolytic genes such as Pgk1, Ldha, Pgam1 and Gapdh; 2, epidermal growth factor receptor tyrosine kinase (EGFR-TK ) - ERBB2, RTK-RAS signaling, RAS activator genes Rgl1, Rasgrp1, Rasgrf1, Rasgrf 2 and Rapgef5 in suppressing the tumor progression that may represent novel targeted therapy for the management of cancer. This review will facilitate to understand the gene expression that inhibits cancer progression and which could serve as a potential molecular target in understanding cancer pathogenesis.

Most striking was increased abundance of the amyloid precursor protein and apolipoprotein B, indicating that loss of GNPTAB function in these cells corresponds with elevation in proteins associated with neurodegeneration. The implication of these findings on lysosomal disease pathogenesis and the emerging neurological manifestations of GNPTAB-related disorders is discussed.

Aberrantly activated Shh pathway leads to the ectopic expression of Pax6 in granular cells, inducing medulloblastoma development. Moreover, Nkx2.2 transcription factor acts as a suppressor of Pax6 during medulloblastoma development and maintenance. Overall, this study provides novel insights for the development of effective therapeutic strategies and suggests potential targets for medulloblastoma.

The review encompasses various CNS tumor types, including subependymal giant cell astrocytoma, chordoid glioma, pituicytoma, ependymomas, astrocytomas, glioblastomas, medulloblastomas, and choroid plexus tumors, highlighting the potential role of TTF-1 in differentiating these neoplasms from other CNS and metastatic tumors. By synthesizing findings from multiple studies, this review underscores the diagnostic value of TTF-1 in the neuropathological evaluation of CNS tumors and suggests directions for future research to refine its clinical application.

Our in vitro data showed BT9 antitumor efficacy in DAOY and D425 cell lines, suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models.

P2, N=100, Recruiting, Medical University of Vienna | Trial completion date: Apr 2026 --> Apr 2030 | Trial primary completion date: Apr 2026 --> Apr 2030

P2, N=25, Recruiting, Fundación de investigación HM | Not yet recruiting --> Recruiting

The PP2A activators employed in this study are ATUX-6156 and ATUX-6954 (diarylmethylcycloamine sulfonylureas), and ATUX-1215 and ATUX-5800 (diarylmethyl-4-aminotetrahydropyran-sulfonamides)...The present investigation offers proof-of-principle data for PP2A-based reactivation therapy for Group 3 MB and provides the first indications that PP2A reactivation may challenge the current paradigm in targeting the 3-stage process of MB LMD. Further investigations of PP2A activators are warranted as these compounds may prove beneficial as therapeutics for MB.

P1, N=12, Not yet recruiting, University of Florida | Initiation date: Sep 2024 --> Dec 2024

P1/2, N=68, Not yet recruiting, Washington University School of Medicine

P2, N=44, Recruiting, Beijing Sanbo Brain Hospital | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Aug 2024 --> Aug 2025

Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in modulation of stemness, neuronal differentiation, and expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in expression of MYC and increase in TP53 .

P2, N=9, Active, not recruiting, National Cancer Institute (NCI) | N=49 --> 9 | Trial completion date: Sep 2024 --> Oct 2025

Blastula-stage zebrafish MB xenografts present an alternative to current MB mouse xenograft models, enabling quick evaluation of tumor cell growth, neurotropism, and drug efficacy.

Our findings support a MYC-induced dependency on the serine/glycine pathway in MBGRP3 that represents a novel therapeutic treatment strategy for this poor prognosis disease group.

MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR "canonical" MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.

P1, N=18, Recruiting, Emory University

This strategy, partly adopted in the ongoing SIOPE protocol,confirmed improved EFS and OS over previously reported outcomes in all high-risk categories;SHH tumors appeared the most aggressive.

This study provides pre-clinical evidence that AKT inhibitors combined with PI3K inhibitors, cisplatin, or vincristine exhibit additive/synergistic anti-MB activity, and lower doses could be used. The latter also applied to one MB line grown as spheroids, further supporting their future potential use.

P1, N=12, Recruiting, Children's National Research Institute | Active, not recruiting --> Recruiting | Trial completion date: Dec 2033 --> Dec 2032 | Initiation date: Jun 2024 --> Sep 2024 | Trial primary completion date: Dec 2032 --> Dec 2030

P2, N=650, Active, not recruiting, St. Jude Children's Research Hospital | Recruiting --> Active, not recruiting

LP-WGS of CSF-derived cfDNA is feasible using a clinical platform, with greater sensitivity for tumor detection compared to conventional CSF cytologic analysis at initial staging. Large prospective studies are needed to further evaluate LP-WGS as a predictive biomarker.

Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

P1, N=21, Active, not recruiting, St. Jude Children's Research Hospital | Trial completion date: Oct 2024 --> Mar 2025

P2, N=128, Active, not recruiting, Pfizer | Phase classification: P1/2 --> P2 | Trial completion date: Feb 2025 --> Oct 2025

Finally, we report two novel E3 ubiquitin ligases, Btbd9 and Kctd3, known Cul3 interactors, as positive Hedgehog pathway regulators. Our data pave the way for a better understanding of the regulation of gene expression and the Hedgehog signaling pathway.

Furthermore, we identified the significance of TKT within the total CSF and its presence within circulating EVs in the CSF. We suggest that TKT may serve as a biomarker for MBL.

Classical variant MB exhibited predominant p53 and cytoplasmic survivin expression. Given the association of survivin and p53 expression with poor prognosis, especially in the prevalent classical variant, targeted therapies may hold promise for MB treatment advancement.

Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

P1/2, N=13, Active, not recruiting, Hospital Infantil Universitario Niño Jesús, Madrid, Spain | Recruiting --> Active, not recruiting

P2, N=26, Active, not recruiting, University of Florida | Trial completion date: Jun 2024 --> Mar 2025

Most cases are sporadic, but well characterized germline alterations in APC, ELP1, GPR161, PTCH1, SUFU, and TP53 predispose to medulloblastoma...Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma.

P2, N=20, Active, not recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Recruiting --> Active, not recruiting | N=205 --> 20 | Trial completion date: Mar 2030 --> Apr 2025 | Trial primary completion date: Mar 2030 --> Apr 2025