|
| Status |
Public on Aug 21, 2012 |
| Title |
Combined PI3K/mTOR and MEK Inhibition Provides Broad Anti-Tumor Activity in Faithful Murine Cancer Models |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
Anticancer drug development is an inefficient process, with potential therapeutics demonstrating a high attrition rate due to lack of efficacy in Phase II/III testing. In an effort to develop improved pre-clinical predictors of efficacy, we and others have turned to testing in genetically engineered murine models (GEMMs) of cancer, which may offer some advantages to in vitro and xenograft systems. Specifically, we assessed the activity of 16 treatment regimens in a Ras-driven, Ink4a/Arf-deficient melanoma GEMM. Like human RAS-mutant melanoma, this GEMM was refractory to standard chemotherapy and single-agent small molecule therapies. Only one regimen exhibited significant anti-tumor activity in this model: combined treatment with AZD6244 (MEK inhibitor) and BEZ235 (dual PI3K/mTOR inhibitor), which produced marked tumor regression and improved survival. Given the surprising activity of the “AZD/BEZ” combination in a melanoma GEMM, we next tested this regimen in a Ras-driven orthotopic-transplant model of “claudin-low” breast cancer, which shares some gene expression features with melanoma. The AZD/BEZ regimen also exhibited significant activity in this related Ras-driven model, leading us to testing in even more diverse GEMMs of basal-like and luminal breast cancer. The AZD/BEZ combination was highly active in each of these distinct breast models, demonstrating equal or greater efficacy compared to any other regimen tested in studies of over 700 tumor-bearing mice. This regimen even exhibited activity in tumors selected for resistance to another effective chemotherapy agent, lapatinib, in HER2+ models. These results demonstrate the utility of credentialed murine models for large-scale efficacy testing of diverse anti-cancer regimens, and predict combinations of PI3K/mTOR and MEK inhibitors will demonstrate anti-tumor activity in a wide-range of human malignancies.
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| |
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| Overall design |
16 array samples
|
| |
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| Contributor(s) |
Roberts PJ, Perou CM, Sharpless NE |
| Citation(s) |
22872574 |
| Submission date |
Feb 10, 2012 |
| Last update date |
Jul 17, 2015 |
| Contact name |
Charles M. Perou |
| E-mail(s) |
cperou@med.unc.edu
|
| Organization name |
University of North Carolina at Chapel Hill
|
| Department |
Professor of Genetics, and Pathology & Laboratory Medicine; Lineberger Comprehensive Cancer Center
|
| Street address |
12-044 Lineberger Comprehensive Cancer Center CB# 7295
|
| City |
Chapel Hill |
| State/province |
NC |
| ZIP/Postal code |
27599-7264 |
| Country |
USA |
| |
|
| Platforms (3) |
| GPL2881 |
Agilent-013326 Mouse Oligo Microarray (V2) G4121B (Feature Number version) |
| GPL10732 |
Mouse-Agilent-22K-D20030711 |
| GPL11383 |
Agi-perou-lab-custom-MM-144K-arrays-BARCODE25503 |
|
| Samples (16)
|
|
| Relations |
| BioProject |
PRJNA152123 |
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