Table Of ContentTargeted Therapies in Cancer:
Myth or Reality?
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research
JOHN D. LAMBRIS, University of Pennsylvania
RODOLFO PAOLETTI, University of Milan
Recent Volumes in this Series
Volume 602
OSTEOIMMUNOLOGY: INTERACTIONS OF THE IMMUNE AND SKELETAL
SYSTEMS
Edited by Yongwon Choi
Volume 603
THE GENUS YERSINIA: FROM GENOMICS TO FUNCTION
Edited by Robert D. Perry and Jacqueline D. Fetherson
Volume 604
ADVANCES IN MOLECULAR ONCOLOGY
Edited by Fabrizio d’Adda di Gagagna, Susanna Chiocca, Fraser McBlane and
Ugo Cavallaro
Volume 605
INTEGRATION IN RESPIRATORY CONTROL: FROM GENES TO SYSTEMS
Edited by Marc Poulin and Richard Wilson
Volume 606
BIOACTIVE COMPONENTS OF MILK
Edited by Zsuzsanna Bosze
Volume 607
EUKARYOTIC MEMBRANES AND CYTOSKELETON: ORIGINS AND EVOLUTION
Edited by Gáspár Jékely
Volume 608
BREAST CANCER CHEMOSENSITIVITY
Edited by Dihua Yu and Mien-Chie Hung
Volume 609
HOT TOPICS IN INFECTION AND IMMUNITY IN CHILDREN VI
Edited by Adam Finn and Andrew J. Pollard
Volume 610
TARGETED THERAPIES IN CANCER
Edited by Francesco Colotta and Alberto Mantovani
A Continuation Order Plan is available for this series. A continuation order will bring delivery of each
new volume immediately upon publication. Volumes are billed only upon actual shipment. For further
information please contact the publisher.
Francesco Colotta
Alberto Mantovani
Editors
Targeted Therapies
in Cancer:
Myth or Reality?
Francesco Colotta Alberto Mantovani
Nerviano Medical Sciences Istituto Clinico Humanitas and
10 Viale Pasteur Institute of Pathology
Nerviano (Milano) 20014, Italy University of Milan
[email protected] 56 Via Manzoni
Rozzano, Milano 20089, Italy
[email protected]
ISBN 978-0-387-73897-0 e-ISBN 978-0-387-73898-7
Library of Congress Control Number: 2007936362
© 2008 Springer Science+Business Media, LLC
All rights reserved. This work may not be translated or copied in whole or in part without the written
permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY
10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in
connection with any form of information storage and retrieval, electronic adaptation, computer
software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.
The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are
not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject
to proprietary rights.
Printed on acid-free paper.
9 8 7 6 5 4 3 2 1
springer.com
Introduction
Cancers share a restricted set of characteristics crucial to the tumor phenotype:
proliferation in the absence of external growth stimuli, avoidance of apoptosis and
no limits to replication, escape from external growth-suppressive forces and the
immune response, an inflammatory micro-environment with new blood vessel
formation, and an ability to invade normal tissues. In the last 20 years, the molecular
determinants of these behaviors are becoming increasingly well understood. This
has changed the current paradigm underlying the drug discovery process intended
to identify novel therapies to fight cancer.
In the past most efforts to identify novel therapies to cancer were focused on the
empirical observation of natural or chemically synthesized molecules that inhibited
cancer cell growth in vitro and/or in vivo. Most often, the molecular mechanisms
underlying the observed anti-cancer activities of empirically discovered anti-cancer
agents were discovered afterwards. Cornerstones of currently used chemotherapeutic
armamentarium have been discovered according to this “ empiricism-based
paradigm.”
The “molecular target paradigm” is focused on the molecular determinants of
aberrant cancer behavior. Conceptually, this paradigm starts with the identification
and molecular characterization of proteins that are mutated or over-expressed in
cancer cells, and that are believed to play a key role in cancer cell biology. High
throughput screening and modern medicinal chemistry, along with sophisticated
techniques like computational chemistry and modeling, lead to rapidly identifying
hits and then leads that specifically and potently inhibit the activity of proteins
mutated or over-expressed in cancer. Recombinant approaches have also been
s uccessfully used to generate molecular-targeted biologicals that specifically hit
proteins aberrantly expressed in cancer cells.
The global effort sustained by the scientific community and the pharmaceutical
industry to discover new approaches to fight cancer is impressive. Thousands of
scientists are devoted to this mission and the global investment is in the order of
several billion Euros. The “targetcentric” paradigm in cancer drug discovery is
widely accepted and used in the pharmaceutical industry and represents the current
standard approach to cancer drug discovery.
In September 2005 an International Meeting on “Targeted Therapies in
Cancer: Myth or Reality” was held in Milan. This successful meeting sponsored by
v
vi Introduction
Nerviano Medical Sciences (www.nervianoms.com) was intended as a forum for
scientists and clinicians working in cancer drug discovery and therapy to share
their reflections and experiences on how the paradigm shift from empiricism to
molecular-targeted therapies is contributing to the translation of basic knowledge
into new therapies for cancer patients. This book collects the contributions given
by scientists and clinicians, from academia and industry, who participated
in this meeting.
We hope that this book contributes to the improvement of our approach to cancer
drug d iscovery and helps us find new, more efficacious and better tolerated drugs
for cancer patients. It provides an overview of diverse approaches ranging from
drug discovery to cellular therapy. Although this change in paradigm has been use-
ful, its entry into the clinical arena was associated with unforeseen problems
including the emergence of resistance, unexpected side effects and failures. Time
is, therefore, ripe for a critical cultural reflection on the state of the art, prospects
and limitations. Ultimately, is targeted therapy in cancer a myth or a reality?
Francesco Colotta
Alberto Mantovani
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Causality in Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Giulio Giorello
The Evolution of the Biomedical Paradigm in Oncology:
Implications for Cancer Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Gilberto Corbellini and Chiara Preti
Anticancer Drug Discovery and Development . . . . . . . . . . . . . . . . . . . . . . 19
Francesco Colotta
Beyond VEGF: Targeting Tumor Growth and Angiogenesis
via Alternative Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
James Christensen and Kenna Anderes
Aurora Kinases and Their Inhibitors: More
Than One Target and One Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Patrizia Carpinelli and Jürgen Moll
Signalling Pathways and Adhesion Molecules as Targets
for Antiangiogenesis Therapy in Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Gianfranco Bazzoni
Developing T-Cell Therapies for Cancer in an Academic Setting . . . . . . 88
Malcolm K. Brenner
vii
viii Contents
Anticancer Cell Therapy with TRAIL-Armed CD34+
Progenitor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Carmelo Carlo-Stella, Cristiana Lavazza, Antonino Carbone,
and Alessandro M. Gianni
Linking Inflammation Reactions to Cancer: Novel Targets
for Therapeutic Strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Alberto Mantovani, Federica Marchesi, Chiara Porta,
Paola Allavena, and Antonio Sica
Clinical Development of Epidermal Growth Factor Receptor (EGFR)
Tyrosine Kinase Inhibitors: What Lessons Have We Learned?. . . . . . . . 128
Manuel Hidalgo
GIST As the Model of Paradigm Shift Towards Targeted Therapy
of Solid Tumors: Update and Perspective on Trial Design . . . . . . . . . . . . 144
Jaap Verweij, Caroline Seynaeve, and Stefan Sleijfer
Monoclonal Antibodies in the Treatment of Malignant
Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Bertrand Coiffier
Molecular Network Analysis using Reverse Phase Protein
Microarrays for Patient Tailored Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 177
Runa Speer, Julia Wulfkuhle, Virginia Espina, Robyn Aurajo,
Kirsten H. Edmiston, Lance A. Liotta, and Emanuel F. Petricoin III
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
1
Causality in Medicine
Giulio Giorello
In the words of the great astronomer John Frederick William Herschel [son of
Friedrich Wilhelm, the scientist of great renown who, with his sister Caroline
Lucretia, discovered the planet Uranus (1781), author of the fundamental text of
philosophy of science Preliminary Discourse on the Study of Natural Philosophy
(1830)], when a “mind” studies any phenomenon that gives rise to a sensation of
wonder or even fear, then the next step must be to find a way to discover what
p roduced that sensation. This, of course, is a hallowed tradition: the famous motto
of Vergil comes to mind, “felix qui potuit rerum cognoscere causas” (Georgics, II,
490), that motto which paraphrases the well-known passage penned by Lucretius in
his De rerum natura (III, 1072). This statement, however, must be revised when
taken in a typically empirical context: the clearest indication that the “true cause”
has been identified is when it not only provides an answer to the original question,
but also offers an explanation of many other facts, sometimes exceeding even the
wildest hopes of the original researchers. (It may even be that on re-examination
what was originally thought to be evidence against a certain hypothesis may turn
out to be quite the opposite).
Herschel, in the tradition of his times, defined as natural philosophy that which
today we call more simply science; but this term caught the Lucretian (or Vergilian)
spirit of the attempt to return “anomalous” events to the regularity of a pattern
which often, though not always, justified rational action. If (a) the cause has been
identified and (b) it is possible intervene, then it is perfectly reasonable to expect
a (desired) change in the effects. This is the logic on which the Greeks based their
techne and the Latins their ars, and the art of medicine (ars medica) can also be
made to fit into this framework. The way in which this has been done over time
represents one of the most important achievements of scientific and philosophical
thought.
It is not necessary to cite all the classic precedents; it is, in fact, sufficient to
mention Claude Bernard’s well-known Introduction à l’étude de la médicine
expérimentale (1865) and the excellence of the empiricist approach that he
Università degli Studi di Milano, Dipartimento di Filosofia, Via Festa del perdono 7 - 20122,
Milano, [email protected]
1
F. Colotta and A. Mantovani (eds.), Targeted Therapies in Cancer.
© Springer 2008
2 G. Giorello
d elineates in its pages. The aim of this discipline is “to preserve health and cure
i llness.” The latter is, in fact, those very “abnormalities” that provoke wonder (and
of which, understandably, people tend to be afraid); it is necessary to know the
causes of the biological phenomena in the normal state (“physiology”) to explain
them. This discipline teaches us to maintain the natural conditions of life as they
are, and by so doing, to conserve health; however it is equally important to have a
working knowledge of illness and “the factors that provoke illness” (“pathology”):
by this means we are able to impede the onset of illness, or at least to fight its
effects with various therapies – in short, it allows us to recover.
Bernard does not restrict his considerations to the simple “experience” of the
sick and of successful healers. Like all good empiricists, and in no way differing
from the great theoreticians like Herschel, for his specific field - which is experi-
mental medicine as a support to therapy - he maintains that the observation of the
pertinent phenomena should be integrated with conjectures which, in turn, have to
be checked with experiments, with true empirical tests. If the practitioner is to be a
true scientist he must first ascertain the facts and formulate a hypothesis; then
ideate an experiment and invent the conditions by which to test his hypothesis. This
experiment will give birth to new phenomena that will draw his attention and cause
him to formulate further hypotheses, and so on. Therefore, we can see that medical
knowledge is an “active” science rather than a mere registration of facts, and this
long before it is applied to each individual patient (“therapy”). This is why disci-
plines such as “physiology” and “pathology” are so important. Bernard flanks his
observations of the conditions of each individual patient with his laboratory work.
This “active” aspect of “experimental medicine” allows the practitioner to adjust
the errors in every day medical practice. He himself wrote that: “Science […]rejects
that which is not determined, and when, as in medicine, one wishes to base one’s
opinions on one’s clinical eye, on inspiration or a somewhat vague intuition, then
one is outside the bounds of science and provides an example of bizarre medicine
which can be the cause of the very worst forms of damage as it entrusts the health
and life of the patient to the vagaries of ignorant visionaries. True science teaches
us to doubt and not to take decisions when knowledge is not present.” In his work
entitled Biologia e medicina tra molecole, formazione e storia (Laterza, Roma-Bari
1991), Giovanni Felice Azzone indicates that it was Claude Bernard who proposed
the causal paradigm in medicine, in a sophisticated process of model building, in
which the models were to be controlled by experiments. This is, in fact, the very
aspect which changes the nature of the intervention in the context of prevention and
in the context of therapy. For Claude Bernard this type of intervention is “rational”
insofar as it is justified by a type of “determinism” that allows us to predict the
effects given the cause. It must be kept in mind, however, that this form of deter-
minism must be interpreted as a methodological premise and not as a metaphysical
foundation: without this premise, science would be completely “impotent” – and an
unbridgeable abyss would open up between medical theory and practice, just as it
was in the days of “empirical medicine,”,which is very different from “experimental
medicine.”
