Resistance to Aromatase Inhibitors in Breast Cancer

ISBN-13: 9783319382845 / Angielski / Miękka / 2016 / 288 str.

Alexey Larionov

Opis

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.

Spis treści

.-1 Clinical Use of Aromatase Inhibitors in Breast Cancer: History and Present

.-2 Structure, Regulation and Polymorphisms of the Aromatase Gene

.-3 Structure, Function and Inhibition of Aromatase

.-4 In Vivo Models of AI Resistance

.-5 Ineffective inhibition of aromatase: a cause for AI resistance?

.-6 Understanding the New Biology of Estrogen-Induced Apoptosis and its Application in Patient Care

.-7 Ligand-independent signalling through estrogen receptor pathways in breast cancer

.-8 Chromatin and epigenetic determinants of resistance to aromatase inhibitors

.-9 Aromatase Inhibitor Resistance via Non-endocrine Signalling Pathways

.-10 Prediction of Response to Aromatase Inhibitors in Breast Cancer

.-11 Clinical Trials Combining Aromatase Inhibitors with Other Targeted Treatments

.-12 Aromatase Inhibitors Beyond Breast Cancer: Endometrium vs Breast Puzzle and Other Issues

O autorze

Alexey Larionov, Ph.D. is a researcher at the Academic Laboratory of Medical Genetics and Statistics and Computational Biology Lab at the University of Cambridge. Dr Larionov is an expert in endocrine resistance in breast cancer, as well as whole exome sequencing data analysis. Dr. Larionov has received over 1019 citations.

Blurb

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.