ArticleMolecular cancer therapeutics2023
Combination of Ribociclib with BET-Bromodomain and PI3K/mTOR Inhibitors for Medulloblastoma Treatment In Vitro and In Vivo.
Article in Molecular cancer therapeutics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 28 citations in OpenAlex.
- A Conserved Enhancer Locus in Extrachromosomal DNA and Homogeneously Staining Regions Activates MYC Transcription in Group 3 Medulloblastoma.Cancer research · 2026Article
- Patient-derived pediatric brain tumor orthotopic xenografts and tumor organoids faithfully recapitulate primary tumors.Science advances · 2026Article
- Multiple patient-derived glioblastoma models reveal synthetic lethality through concurrent PI3K and CDK4/6 inhibition by blocking trans-active cooperation.Neuro-oncology · 2026Article
- Targeting the p53 pathway to treat atypical teratoid rhabdoid tumors.Neuro-oncology pediatrics · 2026Article
- Transcriptional regulation of nucleotide metabolism in medulloblastoma subtypes and prognostic implications analyzed by RNA-Seq.Journal of cancer research and clinical oncology · 2025Article
- Advancing Medulloblastoma Therapy in Pediatrics: Integrative Molecular Classification and Emerging Treatments.Brain sciences · 2025Review
- Small-Molecule Drugs in Pediatric Neuro-Oncology.Current oncology (Toronto, Ont.) · 2025Review
- Genetic modeling of ELP1-associated Sonic hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target.Cancer cell · 2025Article
- Beyond small molecules: advancing MYC-targeted cancer therapies through protein engineering.Transcription · 2025Review
- Targeting protein synthesis pathways in MYC-amplified medulloblastoma.Discover oncology · 2025Review
- Medulloblastoma: biology and immunotherapy.Frontiers in immunology · 2025Review
- Mechanistic insights into medulloblastoma relapse.Pharmacology & therapeutics · 2024Review
- miR-124-3p and miR-194-5p regulation of the PI3K/AKT pathway via ROR2 in medulloblastoma progression.Cancer gene therapy · 2024Article
- Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.Nature communications · 2024Article
- Regulation of PI3K signaling in cancer metabolism and PI3K-targeting therapy.Translational breast cancer research : a journal focusing on translational research in breast cancer · 2024Review
- Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets.Cell death discovery · 2023Review
- Review
- Counteracting Immunosenescence-Which Therapeutic Strategies Are Promising?Biomolecules · 2023Review
- Targeting protein folding in N-Myc-driven medulloblastoma.Molecular oncology · 2023Article
- Potent bromodomain and extraterminal domain inhibitor JAB-8263 suppresses MYC expression and exerts anti-tumor activity in colorectal cancer models.World journal of gastrointestinal oncology · 2023Article
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15 authors at 1 institution in 1 country.
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Abstract
Despite improvement in the treatment of medulloblastoma over the last years, numerous patients with MYC- and MYCN-driven tumors still fail current therapies. Medulloblastomas have an intact retinoblastoma protein RB, suggesting that CDK4/6 inhibition might represent a therapeutic strategy for which drug combination remains understudied. We conducted high-throughput drug combination screens in a Group3 (G3) medulloblastoma line using the CDK4/6 inhibitor (CDK4/6i) ribociclib at IC20, referred to as an anchor, and 87 oncology drugs approved by FDA or in clinical trials. Bromodomain and extra terminal (BET) and PI3K/mTOR inhibitors potentiated ribociclib inhibition of proliferation in an established cell line and freshly dissociated tumor cells from intracranial xenografts of G3 and Sonic hedgehog (SHH) medulloblastomas in vitro. A reverse combination screen using the BET inhibitor JQ1 as anchor, revealed CDK4/6i as the most potentiating drugs. In vivo, ribociclib showed single-agent activity in medulloblastoma models whereas JQ1 failed to show efficacy due to high clearance and insufficient free brain concentration. Despite in vitro synergy, combination of ribociclib with the PI3K/mTOR inhibitor paxalisib did not significantly improve the survival of G3 and SHH medulloblastoma-bearing mice compared with ribociclib alone. Molecular analysis of ribociclib and paxalisib-treated tumors revealed that E2F targets and PI3K/AKT/MTORC1 signaling genes were depleted, as expected. Importantly, in one untreated G3MB model HD-MB03, the PI3K/AKT/MTORC1 gene set was enriched in vitro compared with in vivo suggesting that the pathway displayed increased activity in vitro. Our data illustrate the difficulty in translating in vitro findings in vivo. See related article in Mol Cancer Ther (2022) 21(8):1306-1317.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.