Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer
Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer
复制标题
DOI：
10.1016/j.jsbmb.2007.05.019
复制
发表时间：
2007-08-01
影响因子：
4.1
通讯作者：
Dowsett, Mitch
中科院分区：
文献类型：
--
作者：
Johnston, Stephen R. D.;Martin, Lesley-Ann;Dowsett, Mitch
改善内分泌反应性和防止耐药性的发展是目前许多策略的目标，这些策略正在寻求将芳香化酶抑制剂与针对雌激素受体（ER）阳性乳腺癌各种途径的新药结合起来。芳香酶抑制剂获得性耐药的临床前模型表明，几种信号通路增加，包括肽生长因子信号通路（EGFR, HER2）和mTOR信号通路的激活。这些可能导致内质网依赖性基因转录的相关“串扰”激活，因此，内质网与其他信号通路的双重阻断已成为改善内分泌反应性的一种合乎逻辑的方法。芳香化酶抑制剂的临床策略正在寻求通过与选择性内质网下调剂氟维司汀或各种信号转导抑制剂（STIs）联合来阻止这些途径的激活，包括单克隆抗体（曲妥珠单抗）、针对EGFR或HER2的小分子酪氨酸激酶抑制剂（TKIs）（拉帕替尼、吉非替尼）和mTOR拮抗剂（替西莫司）。今年出现了一些早期临床数据，其中一些方法的结果好坏参半。本文回顾了这些策略的基本原理，并讨论了如果我们在临床中成功地将这些新药与芳香酶抑制剂结合起来需要吸取的教训。(C) 2007 Elsevier Ltd.版权所有。
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. (C) 2007 Elsevier Ltd. All rights reserved.