Table Of ContentWolfgang Link
Principles
of Cancer
Treatment and
Anticancer Drug
Development
Principles of Cancer Treatment and Anticancer
Drug Development
Wolfgang Link
Principles of Cancer
Treatment and Anticancer
Drug Development
123
WolfgangLink
Instituto deInvestigaciones Biomédicas
“Alberto Sols”(CSIC-UAM)
Madrid,Spain
ISBN978-3-030-18721-7 ISBN978-3-030-18722-4 (eBook)
https://doi.org/10.1007/978-3-030-18722-4
©SpringerNatureSwitzerlandAG2019
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart
of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission
orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar
methodologynowknownorhereafterdeveloped.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom
therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse.
The publisher, the authors and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authors or the editors give a warranty, expressed or implied, with respect to the material contained
hereinorforanyerrorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregard
tojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.
ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG
Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland
This book is dedicated to my wife, Ana
Preface
This book explains how current medicines against cancer work and how we find
new ones. This is in a nutshell the content of the current book which is based on
advanced classes in a master’s degree program on “Molecular Mechanisms of
Cancer.”Thispostgraduateprogramincludeslearningmodulesoncelldivisionand
cell cycle, signal transduction,oncogenetic andoncogenomics, genetic toxicology,
cell differentiation and stem cells, microenvironment, tumor progression, and
clinical oncology. The learning module defeating cancer includes two main parts,
one on cancer therapy and the second on drug development. The first part of
Chap. 1 provides an introduction to the major problems we face when we treat
malignant tumors in humans, setting the stage for Chap. 2 with a systematic
overview over the current options of cancer therapy such as surgery, radiation,
immunotherapy and chemotherapy and their corresponding modes of action. In
particular, we focus on standard chemotherapeutic and targeted drugs and explain
howtheywork.InChap.3,wecoverintrinsicandacquiredresistancemechanisms
whichrepresentthemainobstacletoimprovetheclinicaloutcomeofcurrentcancer
therapies. Chapter 4 is dedicated to the discovery and development of novel anti-
cancerdrugs.Thedevelopmentofnewmedicinestotreatcancernowadaysisbased
on our growing understanding of the disease. In order to understand this paradigm
shift, we discuss how medicines have been discovered and developed in the past.
ThestructureofChap.2reflectsthedevelopmentprocessofanewdrugbeginning
withtheidentificationandvalidationofatherapeutictarget,theidentificationofan
inhibitor of the target and its subsequent preclinical and clinical development.
Finally, we describe the approval process by regulatory authorities. Chapter 5
provides a critical examination of the economic aspects of our current system of
developing new medicines and its impact on our societies and on future drug
research. At the end of each chapter, a section with thought questions and further
reading has been added.
Madrid, Spain Wolfgang Link
vii
viii Preface
Acknowledgements IthankJavierPérez(ScientificPhotographyandDrawingFacility,Instituto
deInvestigacionesBiomédicas“AlbertoSols,”whopreparedallthefigures.Iamgratefulforthe
support,inspiration,andpatienceofmyfamily—mywifeAnaandourchildren,Lucia,andPablo.
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1.1 Why Haven’t We Cured Cancer yet? . . . . . . . . . . . . . . . . 1
1.1.2 Cancer Is Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.1.3 Where Do We Stand in Cancer Therapy? . . . . . . . . . . . . . 4
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2 Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.1 Mechanical Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.1.1 Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.2 Physical Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.2.1 Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.2.2 Photodynamic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.2.3 Hyperthermia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.3 Chemical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.3.1 Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.3.2 Targeted Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.4 Biological Treatment: E.g. Immunotherapy and Oncolytic
Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
2.4.1 Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2.4.2 Oncolytic Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
3 Cancer Drug Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.1 Mechanisms Upstream of the Molecular Target . . . . . . . . . . . . . . 78
3.2 Mechanisms at the Level of the Molecular Target . . . . . . . . . . . . 80
3.3 Mechanisms Downstream of the Molecular Target . . . . . . . . . . . . 81
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
ix
x Contents
4 Drug Discovery and Development. . . . . . . . . . . . . . . . . . . . . . . . . . . 87
4.1 Target Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
4.2 Target Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
4.3 Lead Discovery and Optimization . . . . . . . . . . . . . . . . . . . . . . . . 98
4.4 Pre-clinical Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . 118
4.5 Approval Process for a New Drug. . . . . . . . . . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
5 Economic and Social Implications of Modern Drug Discovery . . . . . 137
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Index .... .... .... .... .... ..... .... .... .... .... .... ..... .... 141
Abbreviations
ABC ATP-binding cassette
ADME Absorption, distribution, metabolism, excretion
AIDS Acquired immune deficiency syndrome
ALCL Anaplastic large-cell lymphoma
ALK Anaplastic lymphoma kinase
ALL Acute lymphoblastic leukemia
ATM Ataxia-telangiectasia mutated
BCC Basal cell carcinoma
BER Base excision repair
BLA Biologic license application
BRCA1/2 BReast CAncer genes 1 and 2
CAFs Cancer-associated fibroblasts
CAR Chimeric antigen receptors
CDX Cell line-derived xenograft
CHO Chinese hamster ovary
CLL Chronic lymphocytic leukemia
CML Chronic myelogenous leukemia
CRC Colorectal cancers
CRISPR Clustered regularly interspaced short palindromic repeats
CTCL Cutaneous T-cell lymphoma
CTLA-4 T-lymphocyte-associated protein 4
CYP450 Cytochromes P450
DHFR Dihydrofolate reductase
DLBCL Diffuse large B-cell lymphoma
DLTs Dose-limiting toxicities
DNA-PK DNA-dependent protein kinase
DSB Double-strand breaks
EC Effective concentration
ECM Extracellular matrix
EGFR Epidermal growth factor receptor
xi
