Table Of ContentTherapeutic Progress in Oncology
Health and Patients Set
coordinated by
Bruno Salgues
Volume 2
Therapeutic Progress
in Oncology
Towards a Revolution in Cancer Therapy?
Jacques Barbet
Adrien Foucquier
Yves Thomas
First published 2020 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.
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The rights of Jacques Barbet, Adrien Foucquier and Yves Thomas to be identified as the authors of this
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Library of Congress Control Number: 2019954831
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ISBN 978-1-78630-493-3
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
Chapter 1. Genomics and Epigenetics . . . . . . . . . . . . . . . . . . . . . 1
1.1. DNA, RNA and genetic code . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2. Sequencing and genomics . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.3. Transcriptome and proteome . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.4. Epigenetics, the missing link . . . . . . . . . . . . . . . . . . . . . . . . . 13
Chapter 2. Overview of Cancer Chemotherapy . . . . . . . . . . . . . . . 19
2.1. The introduction of an innovative method . . . . . . . . . . . . . . . . . . 20
2.2. Nitrogen mustards, the first revival . . . . . . . . . . . . . . . . . . . . . . 21
2.3. Anti-metabolites, the potential for chemotherapy
finally revealed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.4. Natural products in the first line . . . . . . . . . . . . . . . . . . . . . . . . 28
2.4.1. Antimitotic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.4.2. Topoisomerase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.5. Cisplatin and organoplatin derivatives . . . . . . . . . . . . . . . . . . . . 32
2.6. An evolving therapeutic approach . . . . . . . . . . . . . . . . . . . . . . 34
2.6.1. Combinatorial chemotherapy . . . . . . . . . . . . . . . . . . . . . . . 35
2.6.2. Adjuvant chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.7. Targeted therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
vi Therapeutic Progress in Oncology
Chapter 3. Immunology and the Immune System . . . . . . . . . . . . . 41
3.1. From variolation to vaccination . . . . . . . . . . . . . . . . . . . . . . . . 42
3.2. The hegemony of the humoral theory . . . . . . . . . . . . . . . . . . . . 44
3.2.1. Instructive theory versus selective theory . . . . . . . . . . . . . . . . 45
3.2.2. Determining the chemical nature of antibodies . . . . . . . . . . . . 47
3.3. Towards a conciliation between cell theory
and humoral theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.4. A complex and specific mode of action of a
so-called adaptive immunity in collaboration
with an innate immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.4.1. The study of organ transplants for a better
understanding of the immune system . . . . . . . . . . . . . . . . . . . . . . 51
3.4.2. The predominant role of MHC molecules
on T cell reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
3.4.3. Other membrane molecules with a key role . . . . . . . . . . . . . . 56
3.4.4. B lymphocytes and antibody production . . . . . . . . . . . . . . . . 57
3.4.5. A collaboration with innate immunity . . . . . . . . . . . . . . . . . . 59
3.4.6. Cytokines, immune system messengers . . . . . . . . . . . . . . . . . 60
3.5. Summary of innate and adaptive immune responses . . . . . . . . . . . . 61
Chapter 4. The Development of Immunotherapy . . . . . . . . . . . . . . 63
4.1. Immunosuppressive treatments for graft tolerance . . . . . . . . . . . . . 63
4.2. Hybridoma techniques for the production of
monoclonal antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.3. Towards an understanding of the immune response
(anti- and pro-tumor) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.3.1. Demonstration of the influence of the immune
system on tumor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.3.2. From the theory of immune surveillance to
the “3 Es” theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.3.3. Antitumor factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
4.3.4. Protumor factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.4. Antitumor immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.4.1. From Coley toxin to bone marrow and hematopoietic
stem cell transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.4.2. From T-cell cultures to antitumor vaccines . . . . . . . . . . . . . . . 74
4.4.3. Monoclonal antibodies: from rituximab to immune
checkpoint inhibitors (ICI) . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
4.4.4. Radioimmunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
4.5. A promising path tending towards improvement . . . . . . . . . . . . . . 78
Contents vii
Chapter 5. The Maturation of Artificial Intelligence . . . . . . . . . . . . 79
5.1. From Babbage machines to the universal Turing machine . . . . . . . . 80
5.2. Cybernetics, for an association between machine
and physiology: towards the development of the
first neural network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.2.1. Cybernetics… . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.2.2. … to connectionism . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
5.2.3. The perceptron, an application of connectionism . . . . . . . . . . . 84
5.3. Cognitivism and the true emergence of
artificial intelligence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
5.3.1. From the Logic Theorist… . . . . . . . . . . . . . . . . . . . . . . . . 87
5.3.2. …to the LISP Language . . . . . . . . . . . . . . . . . . . . . . . . . . 88
5.4. From optimism to the first crisis . . . . . . . . . . . . . . . . . . . . . . . 89
5.4.1. AI in a new momentum . . . . . . . . . . . . . . . . . . . . . . . . . . 89
5.4.2. Technical and theoretical limits finally revealed . . . . . . . . . . . 90
5.5. Expert systems, a renewed interest in AI . . . . . . . . . . . . . . . . . . 92
5.6. The return of neural networks: an optimal method
of automatic learning? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
5.6.1. A renewal of the structure and method of learning . . . . . . . . . . 94
5.6.2. Different types of machine learning . . . . . . . . . . . . . . . . . . . 97
5.6.3. A new wave of hope generated by neural networks
and other learning techniques . . . . . . . . . . . . . . . . . . . . . . . . . . 98
5.7. A new crisis before a decisive rebound . . . . . . . . . . . . . . . . . . . 100
5.7.1. A technological context not yet adapted . . . . . . . . . . . . . . . . 100
5.7.2. A set of factors at the origin of the Big Data era . . . . . . . . . . . . 101
5.8. Deep learning, an association between Big Data and
neural networks: AI in another dimension . . . . . . . . . . . . . . . . . . . . 103
5.8.1. An evolution of structure and power . . . . . . . . . . . . . . . . . . 103
5.8.2. Convolutional networks, surprising performance . . . . . . . . . . . 104
5.8.3. A wide range of applications as a trigger
for investments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
5.8.4. AI as an aid to oncology . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Chapter 6. The Evolution of Cancer Therapy . . . . . . . . . . . . . . . . 111
6.1. Cancer surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
6.1.1. Conventional surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
6.1.2. So-called “minimally invasive” surgery . . . . . . . . . . . . . . . . 113
6.1.3. Image-guided surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
6.1.4. Cryosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
6.1.5. Radiofrequency ablation . . . . . . . . . . . . . . . . . . . . . . . . . . 114
6.1.6. Laser surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6.1.7. Robotic surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
viii Therapeutic Progress in Oncology
6.2. External beam radiotherapy (or external beam
radiation therapy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
6.3. Great innovations in one formula . . . . . . . . . . . . . . . . . . . . . . . 121
6.4. Genomics and epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
6.5. The new therapies of the 21st Century . . . . . . . . . . . . . . . . . . . . 124
6.5.1. Targeted therapies: the use of small inhibitory
molecules (-nib) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
6.5.2. The use of monoclonal antibodies (mAb) . . . . . . . . . . . . . . . 126
6.5.3. CAR T-cells (Chimeric Antigen Receptor) for
customized medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
6.5.4. Vaccine therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
6.5.5. Targeted radionuclide therapy . . . . . . . . . . . . . . . . . . . . . . 131
6.6. Theranostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
6.6.1. The evolution of medical imaging . . . . . . . . . . . . . . . . . . . . 133
6.6.2. The theranostic approach, for a predictive and
personalized medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
6.7. Artificial intelligence (AI) and Big Data . . . . . . . . . . . . . . . . . . . 140
6.8. “In fine” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Preface
As contributors to a research and development organization (Arronax
GIP) that designs and manufactures radiopharmaceuticals for PET (positron
emission tomography) medical imaging and cancer therapy, we felt the need
and motivation to write a synthesis of a possible future of oncology
approaches, to facilitate dialogue both internally and with our multiple
partners from diverse backgrounds.
More generally, this book is intended to popularize new concepts and
corresponding scientific and technological innovations in order to shed light
on the cancer dimension of P4 medicine that is coming: predictive,
preventive, personalized and participatory. It can only be participatory if
patients and their families have a sufficient understanding of the new logics,
issues, therapeutic strategies and machines that are emerging or will emerge
in this field.
Despite our desire to make this book as accessible as possible for readers,
it cannot be devoid of essential technical words that can be found, if
necessary, on hospital websites or on the websites of major organizations
dedicated to medicine and oncology such as the World Health Organization
(WHO), the American Society of Clinical Oncology (ASCO), the National
Cancer Institute (NCI), the Society of Nuclear Medicine and Molecular
Imaging (SNMMI), the Institut national de la santé et de la recherche
médicale (Inserm), the Institut national du cancer (INCa), the European
Association of Nuclear Medicine (EANM), the Radiological Society of North
America (RSNA), the European Society of Radiology (ESR), etc. In addition,
we thought it would be a good idea to add, in some places, web links to videos
of good pedagogical quality, to enhance the readers understanding.
x Therapeutic Progress in Oncology
In addition, the list of abbreviations can be consulted at the end of the
book, and all abbreviated terms are explained in the text when they first
appear.
In order not to be discouraged by the details and possible difficulties of
the initial chapters, impatient readers can go directly to Chapter 6, returning
to the previous chapters if a better understanding is required.
We finish with a warning. In this book we highlight and suggest probable
futures with, of course, the risk of error. Finally, we must draw attention to
this strong rule: we do not provide any advice to patients and have no
legitimacy to suggest medical prescriptions. This is especially the case as
some of the medicines mentioned in Chapter 6 may still be in clinical trials
or may cause more or less controllable side effects at this stage.
Jacques BARBET
Adrien FOUCQUIER
Yves THOMAS
November 2019
