Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer.
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.
- SourceAvailable from: Rabia Gilani[Show abstract] [Hide abstract]
ABSTRACT: Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2. In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ERalpha, HER2, and HIF-1alpha (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ERalpha to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1alpha to determine its importance. Basal HIF-1alpha protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF-1alpha expression in AI-resistant cells is likely regulated by HER2 activated-phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1alpha affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP. One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target.Breast cancer research: BCR 01/2014; 16(1):R15. · 5.88 Impact Factor
Article: Personalizing Breast Cancer Therapy[Show abstract] [Hide abstract]
ABSTRACT: Breast cancer is the most commonly diagnosed cancer in women and accounts for the highest number of cancer related deaths in females worldwide. The disease is attributed to both genetic susceptibility and environmental factors. Several signalling pathways important for development and therapy of breast cancer have been described, including those mediated by the estrogen receptor and BRCA 1 and 2 genes. Intense research efforts have resulted in the identification of other important pathways implicated in breast cancer development including enzymes that control addition and removal of acetyl groups on histone and non-histone proteins such as p300, SRC1 and SIRT family, as well as genes regulating drug disposition and metabolism such as cytochrome P450 (CYP). In addition, cellular processes that can be deregulated in breast cancer including inflammation, hypoxia and energy metabolism have increased understanding of these signalling pathways and have facilitated the discovery of many therapeutic strategies such as selective estrogen receptor modulators and herceptin, which in combination with conservative therapies have increased survival and quality of life. However, the complexity of the disease, the resistance to therapy and the variations between individual breast cancer patients limit the effectiveness of these drugs emphasizing the need to develop novel more precise, predictable and effective individualized breast cancer therapies. Here we discuss signalling pathways contributing to breast carcinogenesis and recent advances towards refining breast cancer subtypes, identifying novel diagnostic and prognostic biomarkers, and developing personalized patient care. Breast cancer is the most common type of cancer and accounts for the second higher mortality rate in women worldwide . The World Health Organisation (WHO) estimates that this number is likely to reach 84 million in the next decade rising at a rate of 5% per year in developing countries if the current speed of production of new therapeutic approaches remains the same . The vast majority of deaths from cancer are not due to the primary tumours, which can be efficiently removed by surgical intervention, but to secondary neoplasm tissues formed because of metastasis . Metastatic tissues are therapeutically challenging since the cause of metastasis differs among individuals . The most common form of breast cancer cases is the sporadic one whereas the inherited form accounts for the 5-10% of all breast cancer cases .Global Journal of Breast Cancer Research. 07/2013; 1(1):8-14.
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ABSTRACT: Modest up-regulation of either HER-ligands or receptors has been implicated in acquired endocrine resistance. AZD8931, a dual tyrosine kinase inhibitor (TKI) of epithelial growth factor receptor (EGFR)/HER2, has been shown to more effectively block ligand-dependent HER signaling than the HER TKIs lapatinib or gefitinib. We therefore examined the effect of AZD8931 in ER-positive/HER2-negative breast cancer cells with acquired resistance to tamoxifen, where there is ligand up-regulation associated with HER pathway activation. RNA-seq ligand profiling and levels of HER receptors and signaling by western blotting were conducted in ER+ MCF7 and T47D parental cells and their Tam-resistant derivatives (TamRes). In vitro cell growth and apoptosis and HER ligand-stimulated signaling were measured in response to endocrine and HER TKIs. For studies in vivo, transplantable MCF7/TamRes xenografts were treated with tamoxifen or fulvestrant, either alone or in combination with AZD8931. AZD8931 only minimally enhanced endocrine sensitivity in MCF7 parental cells, but showed a greater effect in the T47D parental model. AZD8931 combined with either tamoxifen or fulvestrant inhibited cell growth more than lapatinib in T47D TamRes cells, and was also significantly, though modestly, more potent in MCF7 TamRes cells. In both TamRes models, AZD8931 significantly inhibited cell proliferation and induced apoptosis. Under ligand-stimulated conditions, AZD8931 more potently inhibited HER signaling than lapatinib or gefitinib. AZD8931 also significantly delayed the growth of MCF7 TamRes xenografts in the presence of tamoxifen or fulvestrant. The strongest inhibition was achieved with a fulvestrant and AZD8931 combination, though no tumor regression was observed. This study provides evidence that AZD8931 has greater inhibitory efficacy in tamoxifen-resistant settings than in an endocrine therapy naïve setting. The absence of tumor regression, however, suggests that additional escape pathways contribute to resistant growth and will need to be targeted to fully circumvent tamoxifen resistance.Breast Cancer Research and Treatment 02/2014; · 4.47 Impact Factor