Growth factor receptors have long been known to drive malignant transformation and cancer progression. The epidermal growth factor receptor (EGFR, ErbB, HER) system is likely the best described membrane receptor tyrosine kinase family in malignant tumors. With implementation of the growth-inhibitory anti-HER-2 antibody trastuzumab (Herceptin) for the treatment of HER-2-positive advanced metastatic breast cancer, a new era has dawned in the therapy of this malignant disease. Unfortunately, trastuzumab-sensitive cancers invariably develop resistance to the antibody after some time. Recent clinical studies have revealed that these refractory tumors are still responsive to inhibition of the HER receptor family using dual HER-1/-2 inhibitors such as lapatinib (Tykerb/Tyverb). Moreover, a multiplicity of novel, improved irreversibly acting small molecular HER tyrosine kinase inhibitors are in the pipeline of many drug developing companies and are being evaluated in the clinical setting.
Author(s): Maria Sibilia, Christoph C. Zielinski, Rupert Bartsch, Thomas W. Grunt
Series: Milestones in Drug Therapy
Edition: 1st Edition.
Publisher: Springer Basel
Year: 2011
Language: English
Pages: 121
Drugs for HER-2-positive Breast Cancer (Milestones in Drug Therapy)......Page 1
Front-matter......Page 2
Drugs for HER-2-positive Breast Cancer......Page 4
Copyright......Page 5
Drugs for HER-2-positive Breast Cancer: A Major Approval for Translational Cancer Research......Page 6
Reference......Page 8
Contents......Page 10
1 Introduction: Breast Cancer: A Molecularly Heterogeneous Disease......Page 12
2.1 The Receptors and Cognate Growth Factors......Page 13
2.2.2 Signalling Pathways and Transcription Factors......Page 16
3.1 From Linear Pathways to Scale-Free Feedback-Controlled Networks......Page 17
3.2 Clinical Implications of Tumours as Robust Systems......Page 18
3.3.2 Late Feedback Regulation of Transcription......Page 19
4 Aberrant Functions of the ErbB Network in Breast Cancer (see Fig.2)......Page 20
4.1 The Her-2/neu Amplicon......Page 22
4.3 Variant Receptors......Page 23
4.4 Ligands......Page 24
4.5 Adaptor Proteins and Substrates......Page 25
5.1 Aberrations in the PI3K-AKT Pathway......Page 27
5.2.1 Evading the CBL Hub......Page 28
5.2.2 Aberrations in Endocytic Components......Page 29
5.3 Perturbations of Protein and Lipid Phosphatases Acting at and Downstream to ErbB Receptors......Page 30
5.4 Implications to Targeting ErbB Receptors and Their Downstream Pathways......Page 31
6 Outlook......Page 32
References......Page 33
Trastuzumab as Adjuvant Treatment for Early Stage HER-2-positive Breast Cancer......Page 44
1.2 Assessment of Her-2 Status......Page 45
2.2 Mechanisms of Resistance......Page 46
3 Trastuzumab in the Adjuvant Setting......Page 47
3.2 NSABP B-31 and NCCTG N9831......Page 49
3.4 FinHER......Page 50
3.6 Discussion of Adjuvant Trials......Page 51
4 Trastuzumab in the Neo-adjuvant Setting......Page 53
5 Side Effects of Adjuvant Trastuzumab Therapy......Page 54
6 Ongoing Studies......Page 55
References......Page 56
1 Introduction......Page 62
2 Trastuzumab: Clinical Efficacy and Resistance......Page 63
3.2 PTEN and PI3K Signalling......Page 65
3.3 Serum HER-2 Extracellular Domain......Page 66
4 IGF-IR Signalling Pathway in Breast Cancer......Page 67
References......Page 69
1 Introduction......Page 72
2 Mechanisms of Action of Trastuzumab......Page 73
4 Evidence from Retrospective Cohort and Phase II Studies Supporting Treatment Beyond Progression with Trastuzumab......Page 74
5 Phase III Evidence Supporting the Concept of Treatment Beyond Progression with Trastuzumab......Page 76
6 The GBG 26 Treatment Beyond Progression Study......Page 77
9 Conclusion and Future Perspectives......Page 79
References......Page 80
1 Introduction......Page 84
2 The HER Family and Its Role in Cancer......Page 85
3.1.1 Pertuzumab Alone......Page 86
3.1.2 Pertuzumab in Combination with Other Targeted Agents......Page 87
3.2.1 Pertuzumab Monotherapy......Page 89
3.2.2 Pertuzumab Combination Therapy......Page 91
3.3 Clinical Trials in Breast Cancer......Page 92
3.4 Clinical Trials in Ovarian Cancer......Page 95
3.5 Clinical Trials in Other Malignancies......Page 96
4 Conclusions and Future Directions......Page 97
References......Page 98
Beyond Trastuzumab: Second-Generation Targeted Therapies for HER-2-positive Breast Cancer......Page 102
1.1 HER-2 and EGFR/HER1 are ErbB Receptor Family Members......Page 103
1.2 The Role of HER-2 and EGFR/HER1 in Tumourigenesis......Page 104
2.1 Lapatinib......Page 107
2.2 XL647......Page 108
2.4 Neratinib......Page 109
2.6 BIBW 2992......Page 110
3 Conclusion......Page 112
References......Page 113
Index......Page 120
