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Drugs for HER-2-positive Breast Cancer

:	Christoph C. Zielinski, Maria Sibilia, Thomas Grunt
:	Maria Sibilia, Christoph C. Zielinski, Elisabeth Bergen, Thomas W. Grunt
:	Drugs for HER-2-positive Breast Cancer
:	Springer-Verlag
:	9783034600941
:	1
:	CHF 135.20
:

:	Pharmazie
:	English

:	110
:	Wasserzeichen
:	PC/MAC/eReader/Tablet
:	PDF

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.

	Drugs for HER-2-positive Breast Cancer	3
	Preface	5
	Drugs for HER-2-positive Breast Cancer: A Major Approval for Translational Cancer Research	5
	Reference	7
	Contents	9
	The EGFR/ErbB Family in Breast Cancer: From Signalling to Therapy	11
	1 Introduction: Breast Cancer: A Molecularly Heterogeneous Disease	11
	2 Anatomy of the ErbB Network (see Fig.1)	12
	2.1 The Receptors and Cognate Growth Factors	12
	2.2 Intracellular Signalling Pathways Activated by ErbB Receptors	15
	2.2.1 The Adaptors	15
	2.2.2 Signalling Pathways and Transcription Factors	15
	2.2.3 Nuclear Signalling of ErbB Receptors and Ligands	16
	3 ErbB Signalling as a Robust Information Relay System	16
	3.1 From Linear Pathways to Scale-Free Feedback-Controlled Networks	16
	3.2 Clinical Implications of Tumours as Robust Systems	17
	3.3 Feedback Control of the ErbB Network	18
	3.3.1 Early Feedback Regulation	18
	3.3.2 Late Feedback Regulation of Transcription	18
	3.3.3 Late Feedback Regulation of ErbB Signalling	19
	4 Aberrant Functions of the ErbB Network in Breast Cancer (see Fig.2)	19
	4.1 The Her-2/neu Amplicon	21
	4.2 Transcriptional Control of ErbB Receptor Expression	22
	4.3 Variant Receptors	22
	4.4 Ligands	23
	4.5 Adaptor Proteins and Substrates	24
	5 Beyond Receptors and Adaptors: Global Aberrations in ErbB- Regulated Pathways in Breast Cancer	26
	5.1 Aberrations in the PI3K-AKT Pathway	26
	5.2 Perturbations of the Endocytic Machinery in ErbB-Driven Mammary Tumours	27
	5.2.1 Evading the CBL Hub	27
	5.2.2 Aberrations in Endocytic Components	28
	5.3 Perturbations of Protein and Lipid Phosphatases Acting at and Downstream to ErbB Receptors	29
	5.4 Implications to Targeting ErbB Receptors and Their Downstream Pathways	30
	6 Outlook	31
	References	32
	Trastuzumab as Adjuvant Treatment for Early Stage HER-2-positive Breast Cancer	43
	1 Introduction	44
	1.1 Role of Her-2 in Healthy Tissue	44
	1.2 Assessment of Her-2 Status	44
	2 Trastuzumab	45
	2.1 Mechanism of Action	45
	2.2 Mechanisms of Resistance	45
	2.3 Combination of Chemotherapy with Trastuzumab in Advanced Breast Cancer	46
	3 Trastuzumab in the Adjuvant Setting	46
	3.1 HERA	48
	3.2 NSABP B-31 and NCCTG N9831	48
	3.3 BCIRG 006	49
	3.4 FinHER	49
	3.5 PACS 04	50
	3.6 Discussion of Adjuvant Trials	50
	4 Trastuzumab in the Neo-adjuvant Setting	52
	5 Side Effects of Adjuvant Trastuzumab Therapy	53
	6 Ongoing Studies	54
	7 Conclusion	55
	References	55
	Trastuzumab Resistance in Breast Cancer	60
	1 Introduction	60
	2 Trastuzumab: Clinical Efficacy and Resistance	61
	3 Trastuzumab: Mechanisms of Resistance	63
	3.1 Steric Hindrance of Receptor-Antibody Interaction: Over-expression of MUC4	63
	3.2 PTEN and PI3K Signalling	63
	3.3 Serum HER-2 Extracellular Domain	64
	3.4 Amplification of Ligand-Induced Activation of ErbB Receptors	65
	4 IGF-IR Signalling Pathway in Breast Cancer	65
	5 Conclusions	67
	References	67
	Treatment with Trastuzumab Beyond Progression	70
	1 Introduction	70
	2 Mechanisms of Action of Trastuzumab	71
	3 Preclinical Evidence for Treatment Beyond Progression with Trastuzumab	72
	4 Evidence from Retrospective Cohort and Phase II Studies Supporting Treatment Beyond Progression with Trastuzumab	72
	5 Phase III Evidence Supporting the Concept of Treatment Beyond Progression with Trastuzumab	74
	6 The GBG 26 Treatment Beyond Progression Study	75
	7 Further Randomised Trials Exploring Treatment Beyond Progression	77
	8 Trastuzumab Beyond Progression in Combination with Other Targeted Agents	77
	9 Conclusion and Future Perspectives	77
	References	78
	Pertuzumab - a HER-2 Dimerisation Inhibitor - for the Treatment of Breast and Other Cancers	81
	1 Introduction	81
	2 The HER Family and Its Role in Cancer	82
	3 Pertuzumab	83
	3.1 Preclinical Data	83
	3.1.1 Pertuzumab Alone	83
	3.1.2 Pertuzumab in Combination with Other Targeted Agents	84
	3.1.3 Pertuzumab in Combination with Chemotherapy	86
	3.2 Phase I Data	86
	3.2.1 Pertuzumab Monotherapy	86
	3.2.2 Pertuzumab Combination Therapy	88
	3.2.3 Pertuzumab Dosing and Scheduling	89
	3.3 Clinical Trials in Breast Cancer	89
	3.4 Clinical Trials in Ovarian Cancer	92
	3.5 Clinical Trials in Other Malignancies	93
	4 Conclusions and Future Directions	94
	References	95
	Beyond Trastuzumab: Second-Generation Targeted Therapies for HER-2-positive Breast Cancer	99
	1 Introduction	100
	1.1 HER-2 and EGFR/HER1 are ErbB Receptor Family Members	100
	1.2 The Role of HER-2 and EGFR/HER1 in Tumourigenesis	101
	2 Small-Molecule Inhibitors Targeting Both HER-2 and EGFR/HER1	104
	2.1 Lapatinib	104
	2.2 XL647	105
	2.3 AEE788	106
	2.4 Neratinib	106
	2.5 Pelitinib	107
	2.6 BIBW 2992	107
	3 Conclusion	109
	References	110
	Index	116