Article

Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer

Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK.
The Journal of Steroid Biochemistry and Molecular Biology (Impact Factor: 4.05). 08/2007; 106(1-5):180-6. DOI: 10.1016/j.jsbmb.2007.05.019
Source: PubMed

ABSTRACT 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.

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    • "AIs are now first-line treatments for ER + breast cancer in post-menopausal women [6]. However, a significant percentage (range 30% to 65%) of patients either does not respond to AIs [7] or becomes resistant to them [8-10]. "
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    Breast cancer research: BCR 01/2014; 16(1):R15. DOI:10.1186/bcr3609 · 5.88 Impact Factor
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    • "With the increasing number of treatment options for breast cancer patients, therapeutic regimens are becoming more individualized. Pre-clinical data strongly support the rationale for combinatorial therapy (Johnston et al., 2007). However, while some clinical trials combining antiestrogens, EGFR/HER2 inhibitors, anti-angiogenics, and/or chemotherapies have yielded encouraging results (Romond et al., 2005; Polychronis et al., 2005; Tabernero, 2007), others have shown no benefit compared to monotherapy (Leary et al., 2007). "
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    ABSTRACT: Until recently, the study of nuclear receptor (NR) function in breast cancer biology has been largely limited to estrogen and progesterone receptors. The development of reliable gene expression arrays, real-time quantitative RT-PCR, and immunohistochemical techniques for studying NR superfamily members in primary human breast cancers has now revealed the presence and potential importance of several additional NRs in the biology of breast cancer. These include receptors for steroid hormones (including androgens and corticosteroids), fat-soluble vitamins A and D, fatty acids, and xenobiotic lipids derived from diet. It is now clear that after NR activation, both genomic and nongenomic NR pathways can coordinately activate growth factor signaling pathways. Advances in our understanding of both NR functional networks and epithelial cell growth factor signaling pathways have revealed a frequent interplay between NR and epithelial cell growth factor family signaling that is clinically relevant to breast cancer. Understanding how growth factor receptors and their downstream kinases are activated by NRs (and vice-versa) is a central goal for maximizing treatment opportunities in breast cancer. In addition to the estrogen receptor, it is predicted that modulating the activity of other NRs will soon provide novel prevention and treatment approaches for breast cancer patients.
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