Overview
There is now clear evidence that molecular pathways, for example type I receptor tyrosine kinase signalling pathways, modify tumour response to endocrine therapy. HER2 and associated markers are recognised as potential markers for selection of aromatase inhibitors over tamoxifen for the treatment of ER+ve breast cancers. Our ongoing work is focused on identifying key mechanisms of tamoxifen resistance, identifying key predictive biomarkers of relapse on tamoxifen prior to testing the predictive value of such markers in the context of phase III randomised trials to drive patient selection for optimal treatment with different agents available in the clinic. Working with Breakthrough Breast Cancer we will pursue the following projects aimed at extending our understanding of endocrine/tamoxifen resistance.
Project 1: Receptor tyrosine kinases as predictive biomarkers of tamoxifen resistance in early breast cancer
We have extensive evidence that type I receptor tyrosine kinases predict for early relapse of ER positive cancers treated with tamoxifen and this is related to activation of downstream signal transduction pathways. This work has lead to a mathematical modelling of biomakers of tamoxifen response which is being testing in an adjuvant phase III clinical trial (Tamoxifen versus exemestane adjuvant multicentre –TEAM - trial, 5000 cases) which will test the predictive value of these markers for endocrine response. Recent evidence implicates other receptor tyrosine kinases in hormone resistance in breast cancer. FGFR1 (type IV receptor tyrosine kinase) and IGF-1R (type II receptor tyrosine kinase) may drive hormone resistance independently of HER2 in breast cancer. Working with Dr Jorge Reis-Filho in London, we will test the interaction between FGFR1, HER2 and IGF-1R as mechanisms of tamoxifen resistance and as potential predictive biomarkers of tamoxifen resistance in early breast cancer. Markers of FGFR1 gene amplification, activation and expression will be integrated into our mathematical model and if appropriate evaluated as potential predictive markers of endocrine response in the TEAM trial.
Project 2: Molecular profiling of clinically tamoxifen resistant cancers.
Molecular profiling of primary and drug resistant tumours provide an unique opportunity to identify acquired drug resistance pathways where the patient’s primary tumour can act as the ideal control. Such approaches have been extremely powerful in identifying key molecular pathways in hormone resistant prostate cancer. We aim to link with other local Breakthrough researchers (Nick Gilbert/Bernie Ramsahoye) to perform genomic, methylation and transcriptomic profiling of both early and late relapsing breast cancer treated with tamoxifen alone (from an archival population). The combined data from these three platforms will be integrated to identify novel targets for treatment of hormone resistance breast cancer.
Project 3: Association of coactivators and corepressors with endocrine resistance
Differential expression of ER-alpha coactivators (src-1, src-2 and src-3) and corepressors (NCOR1 and SMRT) have been implicated in resistance to endocrine therapy. We will exam the expression levels and relationship of each coactivator and corepressor in breast cancer to identify their role in endocrine resistance and relapse to treatment. We will also investigate the interaction between ER-alpha and each coactivator and their role in breast cancer.
