Related Experiment Video
Updated: Aug 23, 2025
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Combination of Ribociclib with BET-Bromodomain and PI3K/mTOR Inhibitors for Medulloblastoma Treatment In Vitro and In
Barbara Jonchere1, Justin Williams1, Frederique Zindy1
1Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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.
Insights
CDK4/6 inhibitors show promise for medulloblastoma, but drug combinations require further study. In vitro synergy between ribociclib and other agents did not translate to improved survival in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Medulloblastoma treatment remains challenging for MYC/MYCN-driven tumors.
- Intact retinoblastoma protein (RB) in medulloblastomas suggests CDK4/6 inhibition as a potential therapeutic strategy.
- Drug combinations with CDK4/6 inhibitors are understudied.
Purpose of the Study:
- To investigate drug combinations with CDK4/6 inhibitors for medulloblastoma treatment.
- To identify synergistic drug combinations using high-throughput screening.
- To evaluate the in vitro and in vivo efficacy of promising drug combinations.
Main Methods:
- High-throughput drug combination screening of ribociclib (CDK4/6 inhibitor) with 87 oncology drugs in a Group 3 medulloblastoma cell line.
- In vitro testing of drug combinations on established cell lines and primary tumor cells from G3 and SHH medulloblastomas.
- In vivo efficacy studies in medulloblastoma mouse models.
Main Results:
- Bromodomain and extra terminal (BET) and PI3K/mTOR inhibitors potentiated ribociclib's anti-proliferative effects in vitro.
- CDK4/6 inhibitors were identified as potent combination partners for BET inhibitor JQ1.
- Ribociclib demonstrated single-agent activity in vivo, while JQ1 showed limited efficacy due to poor brain penetration.
- Combination of ribociclib and paxalisib (PI3K/mTOR inhibitor) did not improve survival in vivo compared to ribociclib alone.
- Molecular analysis confirmed target engagement but highlighted discrepancies between in vitro and in vivo pathway activity.
Conclusions:
- While in vitro studies show synergy between CDK4/6 inhibitors and other agents like BET and PI3K/mTOR inhibitors, this does not consistently translate to improved in vivo efficacy.
- Challenges exist in translating in vitro drug combination findings to effective in vivo therapeutic strategies for medulloblastoma.
- Further research is needed to overcome barriers such as drug clearance and brain penetration for effective medulloblastoma treatment.
More Related Videos
10:44Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Related Concept Videos
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
01:22PI3K/mTOR/AKT Signaling Pathway
02:56Treatment Resistant Cancers
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:34Inhibition of Cdk Activity
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...