A murine preclinical syngeneic transplantation model for breast cancer precision medicine.
Lorenzo FedericoZechen ChongDong ZhangDaniel J McGrailWei ZhaoKang Jin JeongChristopher P VellanoZhenlin JuMihai GageaShuying LiuShreya MitraJennifer B DennisonPhilip L LorenziRobert CardnellLixia DiaoJing WangYiling LuLauren A ByersCharles M PerouShiaw-Yih LinGordon B MillsPublished in: Science advances (2017)
We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score-based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments.
Keyphrases
- dna damage
- dna repair
- clinical trial
- signaling pathway
- oxidative stress
- cell therapy
- mouse model
- single cell
- machine learning
- childhood cancer
- papillary thyroid
- emergency department
- deep learning
- stem cells
- squamous cell carcinoma
- randomized controlled trial
- gene expression
- drug delivery
- small molecule
- squamous cell
- mesenchymal stem cells
- phase ii
- open label
- breast cancer risk
- protein protein
- study protocol
- amino acid
- combination therapy