Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer.
Date
2007-08Author
Johnston, SRD
Martin, L-A
Leary, A
Head, J
Dowsett, M
Type
Journal Article
Metadata
Show full item recordAbstract
Improving endocrine responsiveness and preventing the development of resistance is the goal of many current strategies that are looking to combine aromatase inhibitors with novel drugs that target various pathways in estrogen receptor (ER) positive breast cancer. Pre-clinical models of acquired resistance to aromatase inhibitors have suggested an increase in several signaling pathways including peptide growth factor signaling (EGFR, HER2) and activation of the mTOR signaling pathway. These may result in associated 'cross-talk' activation of ER-dependent gene transcription, such that dual blockade of ER together with other signaling pathways has become a logical approach to improve endocrine responsivness. Clinical strategies with aromatase inhibitors are looking to prevent activation of these pathways either through combination with the selective ER downregulator fulvestrant, or with various signal transduction inhibitors (STIs) including monoclonal antibodies (trastuzumab), small molecule tyrosine kinase inhibitors (TKIs) against EGFR or HER2 (lapatinib, gefitinib) and mTOR antagonists (temsirolimus). Early clinical data have emerged this year for some of these approaches with mixed results. This article reviews the rationale for these strategies, and discusses the lessons that need to be learnt if we are to successfully integrate these new drugs with aromatase inhibitors in the clinic.
Collections
Subject
Animals
Humans
Breast Neoplasms
Receptor, erbB-2
Aromatase Inhibitors
Drug Therapy, Combination
Signal Transduction
Drug Resistance, Neoplasm
Research team
Endocrine Therapy Resistance
Endocrinology
Language
eng
License start date
2007-08
Citation
The Journal of steroid biochemistry and molecular biology, 2007, 106 (1-5), pp. 180 - 186