Medulloblastoma

Our study also identifies SOX4 upregulation as a major event in later tumor clones for Group 3 and Group 4 MBs, suggesting it as a potential therapeutic target for both subgroups. Taken together, our findings highlight MB's inherent tumor heterogeneity and offer promising insights into potential drivers of MB tumor evolution particularly in Group 3 and Group 4 MBs.

P1, N=11, Completed, Seattle Children's Hospital | Active, not recruiting --> Completed | Trial completion date: Mar 2040 --> Dec 2023 | Trial primary completion date: Mar 2025 --> Dec 2023

P1, N=10, Active, not recruiting, Seattle Children's Hospital | Trial primary completion date: Jul 2024 --> Jul 2025

Compared to the control group, the PBK protein expression levels, cell survival rates, and the number of cells in the proliferative phase were significantly reduced in Control group 1, the PEI group, and the HPAA/siRNA group in both ONS-76 and Daoy cells, with the ONS-76 cells in the HPAA/siRNA group showing the lowest values among these groups (P < 0.05). In summary, the findings indicated that the tumor microenvironment-responsive nanocomposite HPAA/RVG/PBK-siRNA selectively inhibited PBK expression in Daoy medulloblastoma cells, showcasing potential applicability in medulloblastoma therapy.

P1, N=110, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

In ex vivo cultured spontaneous MBs, the expression levels of these genes increase after irradiation in CD1 mice, but not in mice with a C57Bl/6 genetic background, suggesting that this signature could predict tumor response to radiation therapy and help develop strategies for targeting DNA damage repair in tumors. A detailed understanding of the mechanisms behind genetic background-related susceptibility to radiation-induced oncogenic responses is crucial for translational research.

Our findings suggest that integrin-αvβ3 signaling boosts oxidative stress resilience via mTORC1. Thus, targeting integrin-αvβ3 could enhance radiotherapy efficacy in medulloblastoma by inducing ferroptotic cell death.

Importantly, IMP application effectively inhibited the growth of medulloblastoma in vivo, accompanied by the downregulation of GLI1 and phosphorylated STAT3. Our findings revealed IMP as an innovative approach to combat the drug resistance of SMO inhibitors in Hh-driven tumors, highlighting the crucial role of STAT3 as a transcriptional regulator in Hh signaling.

P1, N=20, Recruiting, Valent Technologies, LLC | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=660, Active, not recruiting, St. Jude Children's Research Hospital | Trial primary completion date: Sep 2024 --> Sep 2025

Furthermore, we demonstrated that the combined inhibition of CDK8 and mTOR synergizes to optimize therapeutic outcomes in vivo and in vivo. Overall, our findings establish a connection between CDK8-mediated transcriptional regulation and mRNA translation, suggesting a promising new therapeutic approach that targets the protein synthesis for MYC-driven MB. .

P2, N=23, Not yet recruiting, H. Lee Moffitt Cancer Center and Research Institute

The silencing of caspase-4 confirmed the regulatory role of GBP1 in MB cell pyroptosis. Our findings suggest that NDV elevates IFN-g and GBP1 expression in MB cells, potentially contributing to caspase-4-mediated pyroptosis activation.

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