Effects of combination therapy of a CDK4/6 and MEK inhibitor in diffuse midline glioma preclinical models
Yusuke Tomita1,2, Gabrielle Link3, Yi Ge4,5
1Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
Background:
Diffuse midline glioma (DMG) is an incurable brain cancer without a single FDA-approved drug that prolongs survival. CDK4/6 inhibitors have been evaluated in children with DMG with limited efficacy. Since MAPK pathway activation is upstream of cell proliferation, we hypothesized that MEK inhibitors may increase the anti-tumor effects of CDK4/6 inhibitors. Here, we evaluated the efficacy of the CDK4/6 inhibitor ribociclib and the MEK inhibitor trametinib in human and murine DMG models to investigate combinational effects.
Methods:
We conducted in vitro and in vivo assays using DMG cell lines from human patient-derived xenografts (PDX) and genetically engineered mouse (GEM) models. In vitro, we assessed synergy across human DMG lines. In vivo, we evaluated therapeutic effects with histological examinations, survival analysis, pharmacokinetic measurements, and RNA-sequencing analysis.
Results:
In vitro, ribociclib and trametinib had variable synergistic effects against human DMG cell lines. In vivo, a five-day treatment with combination therapy in the GEM DMG model significantly decreased cell proliferation and increased apoptosis compared with the vehicle, with trametinib having mostly cytotoxic effects and ribociclib having primarily cytostatic effects. In addition, a 21-day treatment with combination therapy significantly prolonged mice survival compared with the vehicle in the GEM DMG model (median survival: 112 days vs. 71.5 days, log rank test p = 0.0195). In an orthotopic PDX model, combination therapy did not prolong mice survival compared with vehicle, ribociclib, and trametinib. LC/MS analysis showed adequate drug delivery across the blood-brain-barrier (BBB) into tumor tissue in both GEM and PDX models. Transcriptomic analysis in the GEM model suggests that combination therapy inhibited the MAPK pathway and inflammation.
Conclusions:
Combination therapy with ribociclib and trametinib significantly prolonged survival in the GEM model but not in the PDX model, highlighting the importance of testing novel therapies in diverse models.
Insights
Combination therapy of ribociclib and trametinib showed promise in extending survival for diffuse midline glioma (DMG) in a mouse model, but efficacy varied across different models.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Diffuse midline glioma (DMG) is an aggressive brain cancer with no FDA-approved treatments.
- Current therapies, including CDK4/6 inhibitors, have shown limited efficacy in pediatric DMG.
- The MAPK pathway's role in proliferation suggests potential synergy with MEK inhibitors.
Purpose of the Study:
- To investigate the combined efficacy of ribociclib (a CDK4/6 inhibitor) and trametinib (a MEK inhibitor) in preclinical DMG models.
- To explore the synergistic effects of this combination therapy on cell proliferation and apoptosis.
- To assess the impact of combination therapy on survival in different DMG models.
Main Methods:
- In vitro synergy assays were performed on human DMG cell lines.
- In vivo studies utilized genetically engineered mouse (GEM) and patient-derived xenograft (PDX) DMG models.
- Therapeutic effects were evaluated through histological analysis, survival studies, pharmacokinetics, and RNA sequencing.
Main Results:
- Combination therapy demonstrated variable synergistic effects in vitro.
- In vivo, the combination significantly reduced proliferation and increased apoptosis in the GEM model.
- A 21-day combination treatment significantly prolonged survival in the GEM model (median 112 days vs. 71.5 days).
- However, combination therapy did not improve survival in the orthotopic PDX model.
- Adequate drug delivery across the blood-brain barrier was confirmed in both models.
- Transcriptomic analysis indicated MAPK pathway and inflammation inhibition in the GEM model.
Conclusions:
- Combination therapy with ribociclib and trametinib shows significant survival benefit in a GEM model of DMG.
- The lack of efficacy in the PDX model underscores the need for diverse preclinical models.
- Further research is warranted to optimize combination strategies for DMG treatment.
Related Concept Videos
02:34Inhibition of Cdk Activity
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...