Resistance to Aromatase Inhibitors in Breast Cancer (Resistance to Targeted Anti-Cancer Therapeutics Book 8)

Aromatase Inhibitors (AIs) treat postmenopausal estrogen receptor positive tumours, which constitute the majority of breast cancer patients. This comprehensive volume brings together the current knowledge from different relevant areas, including molecular mechanisms and translational aspects of drug resistance in AIs. Topics covered include research, experimental , and clinical data specifically focused on AI resistance in breast cancer. The volume will include three sections. The first section covers general knowledge about aromatase inhibitors, including regulation of aromatase genes, and structure and function of aromatase protein. The second section provides the detailed mechanisms of resistance to AIs, while the third section explores prediction of resistance and potential strategies to overcome resistance. Breast cancer is the most common female cancer and AIs significantly improve treatments outcomes compatibly to previously used endocrine treatments. However 10-15% of post-operative patients develop a relapse during adjuvant treatment with AIs; about 25-50% of the patients do not respond to AIs in neo-adjuvant or metastatic setting, and the majority of metastatic patients who initially respond develop resistance within 3 years. There is an important need to understand these mechanisms of resistance in order to develop methods of preventing or overcoming the resistance to AIs, which will ensure a more successful outcome in treating breast cancer.芳香酶抑制剂(AI)可治疗绝经后雌激素受体阳性肿瘤,这种肿瘤占乳腺癌患者的大多数。这本综合卷汇集了不同相关领域的最新知识,包括人工智能耐药性的分子机制和转化方面。涵盖的主题包括专门针对乳腺癌 AI 耐药性的研究、实验和临床数据。该卷将包括三个部分。第一部分介绍芳香酶抑制剂的常识,包括芳香酶基因的调控、芳香酶蛋白的结构和功能。第二部分提供了对人工智能的抵抗的详细机制,而第三部分则探讨了抵抗的预测和克服抵抗的潜在策略。乳腺癌是最常见的女性癌症,人工智能显着改善了治疗结果,与以前使用的内分泌治疗相一致。然而,10-15% 的术后患者在 AI 辅助治疗期间出现复发;大约 25-50% 的患者在新辅助或转移环境中对 AI 没有反应,并且大多数最初反应的转移患者在 3 年内出现耐药性。迫切需要了解这些耐药机制,以便开发预防或克服 AI 耐药性的方法,从而确保乳腺癌治疗取得更成功的结果。 The book brings together current knowledge about molecular and clinical aspects of resistance to aromatase inhibitors (AIs). The topics and features include: The history of development and clinical role of aromatase inhibitors in breast cancer. The structure and function of aromatase gene and protein, including tissue-specific splicing and regulation of the gene, crystal structure of the enzyme, functioning of its active site and structural basis for development of new aromatase inhibitors. Experimental and pre-clinical models of resistance to aromatase inhibitors (including cell lines and xenografts) as well as methods and results of measuring oestrogen concentrations in blood and tumour tissue of breast cancer patients.^Diversity of molecular mechanisms of AI resistance, including (i) ligand-independent signalling through oestrogen receptor pathway, (ii) hypersensitivity to low concentrations of oestrogens, (iii) crosstalk with non-endocrine signalling (including PI3K/mTOR, IGF, GDNF and Myc pathways), (iv) involvement of oestrogen-induced apoptosis and tissue microenvironment (including inflammatory immune cells and adipocytes) as well as (v) the role of epigenetic mechanisms and pioneering factors in ER signalling and AI resistance. Molecular markers and multi-gene signatures to predict response to AIs, clinical trials aimed at preventing or overcoming resistance by combining AIs with novel targeted agents (including AI combinations with HER2, EGFR, mTOR, PI3K, Akt, CDK4/6, FGFR, HDAC, IGF-1, Src, proteosome- and angiogenic- targeting agents). A review of the effects and clinical indications of aromatase inhibitors beyond breast cancer.^Many of the chapters provide extensive historical overviews to connect current knowledge with the history and inner logic of the field. The authorsĺl team includes world-leading experts, making the book an essential resource for scientists developing new treatments for breast cancer and for medics treating breast cancer patients with aromatase inhibitors The book brings together current knowledge about molecular and clinical aspects of resistance to aromatase inhibitors (AIs). The topics and features include: The history of development and clinical role of aromatase inhibitors in breast cancer. The structure and function of aromatase gene and protein, including tissue-specific splicing and regulation of the gene, crystal structure of the enzyme, functioning of its active site and structural basis for development of new aromatase inhibitors. Experimental and pre-clinical models of resistance to aromatase inhibitors (including cell lines and xenografts) as well as methods and results of measuring oestrogen concentrations in blood and tumour tissue of breast cancer patients. Diversity of molecular mechanisms of AI resistance, including (i) ligand-independent signalling through oestrogen receptor pathway, (ii) hypersensitivity to low concentrations of oestrogens, (iii) crosstalk with non-endocrine signalling (including PI3K/mTOR, IGF, GDNF and Myc pathways), (iv) involvement of oestrogen-induced apoptosis and tissue microenvironment (including inflammatory immune cells and adipocytes) as well as (v) the role of epigenetic mechanisms and pioneering factors in ER signalling and AI resistance. Molecular markers and multi-gene signatures to predict response to AIs, clinical trials aimed at preventing or overcoming resistance by combining AIs with novel targeted agents (including AI combinations with HER2, EGFR, mTOR, PI3K, Akt, CDK4/6, FGFR, HDAC, IGF-1, Src, proteosome- and angiogenic- targeting agents). A review of the effects and clinical indications of aromatase inhibitors beyond breast cancer. Many of the chapters provide extensive historical overviews to connect current knowledge with the history and inner logic of the field. The authors' team includes world-leading experts, making the book an essential resource for scientists developing new treatments for breast cancer and for medics treating breast cancer patients with aromatase inhibitors Front Matter....Pages i-xvi Clinical Use of Aromatase Inhibitors in Breast Cancer: History and Present....Pages 1-11 Structure, Regulation and Polymorphisms of the Aromatase Gene....Pages 13-31 Structure, Function and Inhibition of Aromatase....Pages 33-61 In Vivo Models of AI Resistance....Pages 63-86 Ineffective Inhibition of Aromatase: A Cause for AI Resistance?....Pages 87-99 Understanding the New Biology of Estrogen-Induced Apoptosis and Its Application in Patient Care....Pages 101-114 Ligand-Independent Signalling Through Estrogen Receptor Pathways in Breast Cancer....Pages 115-144 Chromatin and Epigenetic Determinants of Resistance to Aromatase Inhibitors....Pages 145-168 Aromatase Inhibitor Resistance via Non-endocrine Signalling Pathways....Pages 169-190 Prediction of Response to Aromatase Inhibitors in Breast Cancer....Pages 191-228 Clinical Trials Combining Aromatase Inhibitors with Other Targeted Treatments....Pages 229-259 Aromatase Inhibitors Beyond Breast Cancer: Endometrium Versus Breast Puzzle and Other Issues....Pages 261-285 Back Matter....Pages 287-288