Pre-clinical evaluation of combination treatments for invasive lobular breast cancer
Worldwide Cancer Research
Royal College of Surgeons in Ireland
Invasive lobular carcinoma (ILC) is the second most common type of breast cancer (approximately 10-15% of all breast tumors). Women with ILC are usually older, used hormone replacement therapy and are more likely to have ER+ disease. Compared to other ER+ breast cancers, ILCs are more likely to metastasize to the peritoneum, gastrointestinal tract, and ovaries and are more frequently bilateral. Like other ER+ breast cancers, anti-estrogen resistance has emerged as a significant problem in the management of ILC, however, ILC is considered to be chemo-resistant and patients receive no additional benefit from chemotherapy. As such, there is a pressing need to develop tailored therapeutic options for endocrine-resistant ILC patients.    As part of the FP7 RATHER project, we discovered that the BET protein Brd3 is a marker of poor prognosis in ILC but not in ER+ breast cancers as a whole. We subsequently validated this in an independent cohort from the METABRIC study. We also found that ILC cell lines that do not respond to anti-endocrine therapy are sensitive to BET inhibition (iBET), either as a single agent, or in combination with an FGFR inhibitor.   Here we aim to progress our in vitro observations to anchor the therapeutic potential of iBET for endocrine-resistant ILC. To achieve this, we will capitalize on the recent discovery that ILC xenograft models can be readily established by mammary intraductal implantation. The efficacy of iBET either as a single agent or in combination with a FGFR inhibitor will be determined. One of our ILC cell models displays de novo resistance to iBET. ChIP-Seq, RNA-Seq and label-free quantitative mass spectrometry-based comparison of this model with our iBET sensitive ILC model will also allow us to dissect the transcriptional plasticity that underlies resistance to iBET and determine how best to overcome these in ILC patients.
5.1 Pharmaceuticals