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mTOR Pathway and mTOR Inhibitors in Cancer Therapy

:	Vitaly A. Polunovsky, Peter J. Houghton
:	Vitaly A. Polunovsky, Peter J. Houghton
:	mTOR Pathway and mTOR Inhibitors in Cancer Therapy
:	Humana Press
:	9781603272711
:	1
:	CHF 193.20
:

:	Nichtklinische Fächer
:	English

:	304
:	Wasserzeichen/DRM
:	PC/MAC/eReader/Tablet
:	PDF

The main objective of this book is to provide an up-to-date survey of the rapidly advancing eld of cancer therapy. Moreover, since our knowledge in this area rapidly evolves, some data have got obsolete during the process of book editing. Our understanding of the mechanisms involved in cancer genesis and progression underwent unprecedented expansion during the last decade, opening a new era of cancer treatment - targeted therapy. The surge in this area results in no small part from studies conducted jointly by basic health scientists and clinical investigators. It is our hope that this book will help foster even further collaboration between investigators in these two disciplines. The target of rapamycin (TOR) was rst identi ed in Saccharomyces cerevisiae and subsequently in mammals (mTOR) as a conserved atypical serine/threonine kinase. In mammalian cells, mTOR exists in at least two multi-protein complexes that have critical roles in regulating cellular homeostasis and survival. As with many other areas of science, discovery of TOR signaling was fortuitous. Rapamycin was isolated as a product of the soil bacteria Streptomyces hygroscopicus, identi ed in a soil sample taken from the island of Rapa Nui (Easter Island). Rapamycin was rst discovered to be a potent antifungal agent and next as an immune suppressive drug. It was only later that it was found to be active as an antitumor agent in non-clinical models; although it was not developed for this indication. The history of rapamycin presents one of the rst examples of chemical genetics.

	Preface	6
	Contents	8
	Contributors	10
	mTORC1: A Signaling Integration Node Involved in Cell Growth	12
	1 Introduction	13
	2 The Domain Structure and Protein Complex Assembly of mTOR	13
	3 Cellular Signaling Upstream of mTORC1: Integration of Anabolic and Catabolic Cues	15
	3.1 Growth Factor Signaling	15
	3.2 Nutrients	21
	3.3 Stress Signals	23
	4 Downstream Targets of mTORC1 Regulate Cell Growth Control	26
	4.1 mRNA Translational Control	26
	4.2 Ribosomal Biogenesis	31
	5 Conclusion	33
	References	34
	The Regulation of the IGF-1/mTOR Pathway by the p53 Tumor Suppressor Gene Functions	48
	1 The p53 Pathway	48
	2 The Coordinate Regulation Between the p53 and IGF-1/mTOR Pathways	51
	3 The p53 Regulation of Energy Metabolism	54
	4 Summary	56
	References	57
	mTOR Signaling in Angiogenesis	60
	1 mTOR Signaling in Angiogenesis	62
	1.1 Tumor Angiogenesis	62
	1.2 mTORC1 Signaling: Upstream Activation of Angiogenesis	63
	1.3 The Role of mTOR Signaling in Downstream Endothelial Cell Signaling	66
	1.3.1 VEGF/VEGF-R-Mediated Signaling in Endothelial Cells	66
	1.3.2 Regulation and Function of the PI3K/Akt/mTOR Pathway in Endothelial Cells	67
	1.3.3 PI3K/Akt/mTOR Signaling Pathway in Tumor Angiogenesis	69
	1.4 mTOR Kinase as a Therapeutic Target in Tumor Angiogenesis	71
	1.5 Malignant Diseases Associated with Activated Angiogenesis Due to Disturbance of mTOR Signaling	72
	1.6 mTOR: Integrating Inflammation and Tumor Angiogenesis	77
	1.7 mTOR and Lymphangiogenesis	77
	1.8 Targeting Angiogenesis by mTOR Inhibitors	79
	References	81
	mTORC1 Signaling and Hypoxia	86
	1 Introduction	87
	2 mTORC1 Signaling Is Regulated by Oxygen Levels	87
	3 mTORC1 Regulation by Hypoxia Requires the TSC1/TSC2 Complex	88
	4 The Energy Signaling Kinase AMPK Is Dispensable for mTORC1 Inhibition by Hypoxia	91
	5 The REDD1 Protein Is an Important Mediator of mTORC1 Inhibition by Hypoxia	92
	5.1 Identification of the REDD1 Orthologues Scylla and Charybdis	92
	5.2 REDD1 Is Induced by Hypoxia and Is Both Necessary and Sufficient for mTORC1 Inhibition	93
	5.3 Hypoxia-Independent Regulation of REDD1	95
	5.4 REDD1 in Cancer	97
	6 Other Hypoxia Effector Pathways	99
	7 A Negative Feedback Loop: HIF-1 Regulation by mTORC1	100
	References	101
	mTOR Signaling in Glioblastoma: Lessons Learned from Bench to Bedside	109
	1 Introduction: mTOR Signaling in Glioblastoma	109
	2 Constitutive PI3K Pathway Activation Is a Hallmark of Glioblastoma	110
	3 mTOR as a Therapeutic Target in GBM	111
	4 Targeting the EGFR/PI3K/mTOR Signaling Pathway in Glioma Patients in the Clinic Lessons Learned	113
	5 Pathway Cross Talk and Feedback Loops in Patients	115
	6 Dual PI3K/mTOR and a Role for mTOR/Erk Inhibition	115
	7 mTOR at the Interface of Signal Transduction and Cellular Metabolism	116
	8 Concluding Thoughts	117
	References	118
	mTOR and Cancer Therapy: General Principles	122
	1 Introduction	122
	2 Activation of the PI3K/mTOR Pathway in Cancer	124
	2.1 Amplification/Overexpression of Growth Factor Receptors	124
	2.2 Activation of the PI3K Catalytic Subunit p110	125
	2.3 PTEN Mutation/Deletion/Silencing	126
	2.4 AKT Amplification	127
	2.5 TSC/LKB Mutations	127
	3 Rheb Amplification/Overexpression	128
	3.1 Alterations Downstream of mTORC1 in Cancer	128
	4 Cooperation Between the PI3K/mTORC1 Pathway and Other Oncogenes in Tumorigenesis	129
	5 mTORC1 Signaling in Solid Tumors	129
	5.1 Regulation of mTORC1 by Cellular Stress	129
	5.2 mTORC1 Signaling in Survival	130
	5.3 Role of mTORC1/C2 Signaling in Motility and Invasion	131
	6 mTOR Signaling in Angiogenesis	131
	7 mTOR in Tumor Stem Cells	132
	8 mTOR Signaling in Drug Resistance	133
	8.1 Resistance to Cancer Chemotherapeutic Agents	133
	8.2 Resistance to Molecularly Targeted Agents	134
	9 Concluding Remarks	134
	References	135
	mTOR and Cancer Therapy: Clinical Development and NovelProspects	141
	1 Introduction	141
	2 mTOR Inhibitors Entered in Clinical Trials	142
	3 Dose and Schedule Impact on Toxicity of Rapalogs	143
	4 Pharmacokinetics of Rapalogs	144
	5 Current Imaging of the Antitumor Effects of Rapalo