Background

The major improvement in breast cancer survival in the last two decades is due to the use of targeted therapeutics (tamoxifen in hormone-receptor-positive cancers, trastuzumab in HER2-amplified disease). To further improve breast cancer outcomes, new targeted agents are needed for triple negative breast cancers (TNBC) for which there is no effective therapy. Hedgehog (Hh) signalling is active in TNBC, predicts poor prognosis and drives an aggressive, metastatic phenotype in animal models. The aim of this preclinical study is to evaluate the efficacy of LDE225 (Hh inhibitor) in combination with docetaxel in mice bearing TNBC patient derived xenographs.  Successful completion of this study will trigger the development of phase I and II clinical trials in TNBC patients.

Methods

Immunodeficient NOG mice implanted with two different TNBC xenographs were randomised to 4 treatment arms: vehicle, LDE225, docetaxel, and LDE225 plus docetaxel. Treatment continued for 4 weeks and mice were aged to ethical endpoint. Primary endpoint was tumour growth. Overall survival and metastatic burden were also reviewed but the study was not designed to evaluate these.

Results

LDE225 plus docetaxel led to significant retardation in tumour growth (p<0.0001) and improved overall survival in both TNBC xenograph models compared with monotherapy.  Metastatic burden was also lowest in the combination therapy group. Immunohistochemistry evaluating histological changes, in vitro studies to examine cellular response and microarray profiling to identify molecular changes to treatment are in progress.  

Conclusions

The Hh inhibitor, LDE225 in combination with docetaxel is effective in the treatment of TNBC.