Principles of Molecular Oncology

429 Pages·2008·21.284 MB·English

by  Miguel H. Bronchud MD, PhD (auth.), Miguel H. Bronchud MD, PhD, Mary Ann Foote PhD, Giuseppe Giaccone MD, PhD, Olufunmilayo Olopade MD, Paul Workman PhD (eds.)

Principles of Molecular Oncology
Principles of Molecular Oncology
Third Edition
Edited by
Miguel H. Bronchud, MD, PhD
Hospital General of Granollers, Barcelona, Spain
MaryAnn Foote, PhD
MA Foote Associates, Westlake Village, CA
Giuseppe Giaccone, MD, PhD
National Cancer Institute, Bethesda, Maryland
Olufunmilayo Olopade, MD
University of Chicago Medical Center, Chicago, IL
Paul Workman, PhD
CRC Center for Cancer Therapeutics, Surrey, United Kingdom
Foreword by
Karen Antman, MD
Clinical Dean and Provost, Boston University School of Medicine
Boston, MA
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Foreword
The global shared vision for oncology is prediction and pre- (Data mining of genome-wide scans is a current example of the
vention of cancer rather than the paradigm of the past, diagno- value of observational studies compared to hypothesis driven
sis and treatment. Examples available today include vaccines research.) Observations of breast cancer responses to oopho-
for hepatitis and human papilloma virus to prevent hepatoma rectomy (Beatson, Lancet. 1896;2:104–107) and of responses
and cervical cancer respectively, avoidance of cervical cancer of prostate cancer to estrogens (Huggins and Hodges, Cancer
by removal of premalignant lesions found on Pap smear or Res. 1941;1, 203) established systemic hormonal therapies of
colonoscopy and polypectomy for prevention of colon cancer. today. The use of alkylating agents in lymphoma derived from
In the future, the use of genome wide scans to determine risks, observations of lymphopenia in soldiers after accidental expo-
followed by interventions to prevent or at least delay the emer- sure to sulfur mustards stockpiled for use in World War II.
gence of disease provides a model not only for cancer but also Nevertheless, the characteristic of the cancer research of the
for other life-threatening diseases. past as exclusively “empiric” is inaccurate. The development
Many new molecularly targeted diagnostics and therapeu- of systemic treatment for cancer over the second half of the
tics described in this text, developed based on the rapid growth 20th century is a tribute to the creativity of cancer investiga-
in our understanding of the molecular basis of cancer, already tors and their application of the science of their time. Once the
substantially improve survival of patients with previously lethal antitumor effect of nitrogen mustard was recognized, medici-
malignancies, and also improve quality of life because of fewer nal chemists constructed cyclophosphamide as a prodrug
toxicities. Clearly research in academia and in the pharmaceuti- intended to be metabolized within tumor cells and created l
cal industry is likely to continue to identify “drugable” targets phenylalanine mustard to target the production of melanin in
and construct new diagnostics and therapeutics. melanoma cells. Both drugs proved effective in cancer despite
Balancing this optimistic vision for the future control of can- metabolism and mechanisms in vitro that turned out to be dif-
cer is the complexity of the cancer problem—both the cancer ferent from those planned. Molecularly targeted drugs simi-
itself at the molecular level, but also globally at the social and larly do not always perform as planned. The quintessential
political level. The public perceives cancer as a single disease example of targeted therapy, imatinib (Gleevec) was developed
and desires “a cure for cancer.” Actually, hundreds of malig- to target the PDGF (Platelet-derived Growth Factor) recep-
nancies have been identified by traditional diagnostic methods. tor tyrosine kinase but clinically proved most useful in CML
Even within common cancer categories such as breast or colon (Chronic Myeloid Leukemia) (with translocations involving
cancer, however, subclassifications (and now molecular subclas- c-abl) and gastrointestinal stromal tumors (GIST, with mutated
sifications) exist. Whether each patient’s cancer will ultimately c-kit). Natural products, the class of drugs that were developed
prove to be unique, or whether cancers will fall into a reasonable empirically based on screening have, in fact, proved effective
number of groups for which treatment can be targeted based on in the treatment of many common malignancies. Both targeted
affected molecular pathways is as yet unknown. hypothesis-driven drug development and empiric observations
are likely to provide important leads in the future.
Past as Prologue
Essential Collaborators
Enthusiasts have compared current “targeted” therapies with
“empiric” therapies of the past. Certainly the relative value of Despite progress in our understanding of carcinogenesis and the
hypothesis generated research versus observations and empir- targets for its treatment, cancer remains a major public health
icism has been debated. Each has provided major advances. problem globally in developed and developing nations. Patients
v
vi Foreword
present with lesions comprising more than 1010 tumors cells. Solving the cancer problem will require collaborations
Sections of the tumor or metastases do not necessarily have of scientists both in academia and industry, individuals in
identical molecular signatures. Clearly the wish for the simplic- g overnment (research dollars, health policy and regulatory risk
ity of a single magic bullet targeting a single pathway seems reduction), and public health as well as clinical oncologists.
unrealistic today based on our emerging knowledge of the regu- New effective anticancer agents will have to be affordable for
latory intranet of the cell and the need for disruption of multiple both developed and developing countries. Cancer incidence
pathways for a cancer to emerge. Combinations of systemic and mortality are falling in many developed countries but
agents can target multiple components of the regulatory system rising in developing countries. Progress has been significant
of the cancer cell but also decrease the chance of emergence of but considerable challenges remain.
resistant tumor clones. Avoiding the emergence of resistance
provides the rational for combinations for both cancers and of Karen Antman, MD
infectious diseases such as TB or AIDS. To date combinations Clinical Dean and Provost
are generally required for the cure of malignancies. Boston University School of Medicine
Foreword to the Second Edition
The second edition of Principles of Molecular Oncology is lar discoveries relating to the diagnosis, prevention, early
published 200 years after the exposition of Dalton’s atomic detection, and new treatments are the subject of this book.
theory of matter and 50 years after Watson and Crick Progress in the field of molecular oncology has been much
described the basic structure of DNA. This edition comes less faster than previously imagined because of the abundance of
than four years after the first and is a consequence of the pace innovative technology. High throughput technology for gene
of discovery in such an exciting field of research. In the first sequencing and expression, including comparative genomic
edition it was anticipated that the publication of the sequenced hybridization, proteomics, and proteoglycan research,
human genome would appear in the middle of the first decade has already allowed the study of biologic function using
of the 21st century. It was published in 2001 and already sequenced DNA, RNA, protein, and oligosaccharide mol-
sequenced genomes for several viruses, bacteria, plants, and ecules. We are already awash with data and the new subject
animals are available. In 1844 Darwin wrote to a friend, “at of bioinformatics has been developed to bring some order to
last gleams of light have come and I am almost convinced the problem.
(quite contrary to the opinion I started with) that species are Poincaré, the famous French mathematician, knew from
not (it is like confessing a murder) immutable”. His The the work of Newton that the behavior of 2 bodies acting in a
Origin of Species issued in 1859 provided evidence for the gravitational field could be explained with reasonable accu-
evolutionary theory of life and represented one of the most racy using simple mathematics but the behavior of 3 bodies
important discoveries in biology. was much more difficult to describe. He spent an important
The controversy surrounding Darwin’s theory resulted in part of his working life on this problem and his eventual
the famous debate between Bishop Wilberforce and Thomas model was inaccurate. Understanding the function of genes
Huxley. When Wilberforce finished his long tirade against is the key to the rational development of new treatments, but
the theory, Huxley replied tersely “I have come here in the though some cancers are the result of an altered function of
cause of science only” and went on to demolish the Bishop’s a single dominant gene, many arise from a more complex
argument. The two men had very different backgrounds in interaction between genes. New mathematics is being devel-
education. Scientific method has continued to be the corner- oped to help understand the complexity of these biologic
stone in the study of life and human disease. The discovery systems.
of the structure and chemistry of DNA and the subsequent In spite of the complexity, important information has been
genetic research by many scientists have led to a much bet- provided using molecular techniques, allowing substan-
ter understanding of the mechanisms of human biology and tial improvement in management of patients with cancer.
evolution and of the function of genes. The last 50 years has Improvements have included the identification of predisposi-
been a golden era in this important field with enormous conse- tion to some forms of cancer, more accurate diagnostic and
quences for applied medicine. Darwin of course knew nothing prognostic information, new markers for analyzing tumor
of genes; the processes he described were those of trial and progression, a quantified assessment of minimal residual
error taking place over a vast time scale. disease, and the rational development of new treatments and
Recent discoveries in human genetics have not been with- methods of prevention. Information on all these aspects of
out controversy, but clinical research has benefited from the cancer care has been updated in this new edition. It is gratify-
move away from trial and error to a more rational approach ing to see that a collaborative approach between scientists in
in the development of new patient management techniques many fields is being rewarded by so much progress in the field
for many medical conditions. The techniques involved are of human cancer care. As an undergraduate at Cambridge in
being applied in the study of human cancer and the molecu- the1950s, I had the advantage of contact with Crick, Brenner,
vii
viii Foreword to the Second Edition
Sanger, and Perutz, each of whom provided some insight into References
what was to come. Although since this time progress has
Charles Darwin “Recapitulation and Conclusion,” from The Origin
been logarithmic, there is a great deal that remains a chal-
of Species (1859): Appleton-Century-Crofts Inc.
lenge for future e ditions of this book. Principles of Molecular
John Dewey “The Influence of Darwinism on Philosophy,” from The
Oncology provides v aluable information for the continuing
Influence of Darwinism on Philosophy and Other Essays (1910),
education of all oncologists.
reprinted from the Popular Science Monthly (July 1909), Henry
Holt & Co.
Derek Crowther, PhD, MB BChir, FRCP, FRCR
Emeritus Professor of Medical Oncology
University of Manchester and Christie Cancer Centre
Foreword to the First Edition
At the midpoint of the 20th century, our knowledge of cancer in the past. Optimism is based on the firm belief that under-
was based on epidemiology and pathology, and treatment standing at the molecular level will lead to better and earlier
consisted of surgery and radiation therapy. At mid-century, diagnosis, to new forms of treatment, and, most importantly,
Medawar and colleagues initiated the understanding of trans- eventually to prevention ofmany types of cancer.
plantation immunology, Farber described the first use of an Principles of Molecular Oncology provides a bold new look
antifolic drug to treat leukemia, and Jacobson and coworkers at the evolution of our knowledge of cancer. Authors from
described the irradiation-protection effect of spleen cells. many disciplines are bringing together the facets that provide
These observations opened the door to the development of a comprehensive view of the whole. In a field progressing as
chemotherapy and transplantation in the treatment of cancer. rapidly as the understanding of cancer at the molecular level,
Despite the rapid development of these new disciplines, any book must be regarded as a report of work in progress.
progress was usually based on empiric observations and clini- The reader will enjoy the opportunity to pause and look at
cal trials. the whole field as it stands today. This book will prove both
The rapid advances in molecular biology at the end of the informative and intellectually satisfying.
20th century mark a new era in our knowledge of cancer.
Molecular immunology, molecular genetics, molecular phar- E. Donnall Thomas, MD
macology, and the Human Genome Project are in the process Fred Hutchinson Cancer Research Center
of providing a level of understanding of cancer undreamed of Nobel Laureate in Medicine/Physiology, 1990
ix
Foreword to the First Edition
A famous London surgeon is quoted as saying that a cure for tion of mutations in one or more oncogenes that we acquire
cancer would not bediscovered by people in white coats d uring our lifetime. Since at least some of these may result
working in laboratories, but rather by somebody leaning from specific chromosomal changes, or from the action of
over a fence watching workmen digging a hole in the environmental carcinogens, these observations provide an
ground. Indeed, the ideathat malignant disease might have a elegant synthesis of several different fields of research. So
single cause was rife until quite recently. But untilthe era of although the final details of how a cell becomes cancerous
molecular biology, and the remarkable insights into cell still remain to be worked out, at last we have a blueprint of
biology that followed,the cancer field was in the doldrums. where to go in the future.
Viruses as the cause of human cancer had come and gone, Although it is true to say that the clinical impact of the
chemical carcinogens and exposure to ionizing radiation remarkable advances in molecular medicine of the last few
seemed to be unlikelycauses of the bulk of human cancers, years may still be some time in the future, and that their
and it was not at all clear where to turn in cancer research. immediate benefits have been oversold to the public, there
However, in the 1960s, two fields of investigation started to seems little doubt that these new discoveries will play a
yield results that at least held some promise. Epidemiological major role in the cancer field in the future. The molecular
studies showed quite unequivocally that there is a relation- approach is likely to provide a wide range of extremely
ship between the development of certain cancers and cigaret v aluable diagnostic agents for both the early recognition and
smoking. And at least some forms of leukemia appeared to assessment of the prognosis of different forms of cancer. It
be associated with specificchromosomal changes. However, also seems likely that gene therapy, something that has been
until the advent of recombinant DNA technology, there was “just around the corner” for far too long, will find some of
no indication as to how these observations might be its early applications in cancer treatment. Thus, although
c onnected or about the cellularmechanisms of malignant molecular biology has shown us that cancer is an extremely
transformation. complex disease, and that there are multiple routes to the
When historians of science look back on the close of the neoplastic phenotype, there is little doubt that much of this
20th century and try toevaluate the fruits of the applica- work will find application in the clinic in the not too distant
tion of molecular and cell biology to the study of human future.
disease, it is likely that they will pinpoint the better under- All these aspects of this complex and rapidly mov-
standing of the biology of cancer as one of the highlights ing field are covered in this excellent book, Principles of
of this period. The discovery of oncogenes, together with Molecular Oncology. Clinical oncologists will find a series
improvements in cytogenetics, resulted in an amalgama- of balanced reviews of the current state-of-the-art of the
tion of these two fields of research and led to the dawning diagnosis and treatment of cancer based on molecular tech-
of an understanding of how cancers might result from the nology, and, since cancer touches almost every field of
breakdown of normal cellular homeostatic mechanisms. clinical practice, s pecialists in other disciplines will find
Subsequently, the elucidation of the genetic control of the a very lucid and r eadable account of what is happening in
cell cycle, and how certain oncogenes monitor different one of the genuine success stories of today’s molecular
aspects of cellular activity, allowing cells to go into cycle medicine.
or directing them toward apoptosis, has started to provide Writing a foreword for a book for one of one’s former
some insights into the cellular mechanisms of malignant students, while a constant reminder of the closeness of per-
disease. Almost overnight, cancer has become less mysteri- sonal dissolution, is still an enormous pleasure. If noth-
ous. It is clear that in many cases it results from the acquisi- ing else, it is reassuring to see that at least a few resistant
xi