PRAISE
“In this meticulously detailed chronicle, science writer Wapner recaps the remarkable development of Gleevec, a cutting-edge drug capable of beating the typically fatal cancer of white blood cells known as chronic myeloid leukemia (CML). . . . Her gracefully written history skillfully combines both the science and humanity of this fascinating search for a cure for CML.”
—Publishers Weekly
• • •
“Wapner weaves together the basic and applied science with the stories of the dedicated researchers, the broader supporting superstructure of modern medicine and the process of bringing pharmaceuticals to market. . . . An absorbing, complex medical detective story.”
—Kirkus Reviews
• • •
“The story of the Philadelphia chromosome is truly the story of modern cancer biology—from the very earliest description of a chromosomal abnormality in cancer cells to the development of a targeted medicine against a formerly lethal type of leukemia. Jessica Wapner stitches the whole story together with tenacity, diligence (and humor). This is a wonderful, readable, and highly informative book.”
—Siddhartha Mukherjee, Pulitzer Prize–winning author of The Emperor of All Maladies
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“Jessica Wapner shows us in The Philadelphia Chromosome how the past and the future combine to dramatically change the course of a disease. This beautifully written book is a blueprint for broader healthcare change. A pivotal book.”
—David B. Agus, MD, Professor of Medicine and Engineering, University of Southern California, and author of The End of Illness
• • •
“Jessica Wapner has done two kinds of hard work gracefully: the hard work of understanding cancer genetics and the hard work of rendering that subject into human narrative, lucid explanation, and metaphor. The Philadelphia Chromosome is not just an urgently useful book. It's also an elegant one, put together like a Swiss watch.”
—David Quammen, author of Spillover: Animal Infections and the Next Human Pandemic
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“The Philadelphia Chromosome clearly explains how a half-century’s worth of research transformed a viciously lethal form of cancer into a chronic, treatable condition. Jessica Wapner’s meticulously researched book is both a real-life medical thriller and an engaging narrative about the history of modern cancer research.”
—Seth Mnookin, author of The Panic Virus: The True Story Behind the Vaccine-Autism Controversy
• • •
BECAUSE EVERY BOOK IS A TEST OF NEW IDEAS
the Philadelphia
Chromosome
A Mutant Gene and the Quest to Cure Cancer at the Genetic Level
JESSICA WAPNER
Foreword by Robert A. Weinberg, PhD
New York
The Philadelphia Chromosome:
A Mutant Gene and the Quest to Cure Cancer at the Genetic Level
Copyright © Jessica Wapner, 2013
Foreword copyright © Robert A. Weinberg, PhD, 2013
The photo credits are a continuation of this copyright page.
All rights reserved. Except for brief passages quoted in newspaper, magazine, radio, television, or online reviews, no portion of this book may be reproduced, distributed, or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or information storage or retrieval system, without the prior written permission of the publisher.
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Library of Congress CIP data
Wapner, Jessica.
The Philadelphia chromosome : a mutant gene and the quest to cure cancer at the genetic level / Jessica Wapner ; foreword by Robert A. Weinberg.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-61519-067-6 (pbk.) -- ISBN 978-1-61519-165-9 (ebook)
I. Title.
[DNLM: 1. Leukemia, Myelogenous, Chronic, BCR-ABL Positive--history--United States. 2. Philadelphia Chromosome--United States. 3. Fusion Proteins, bcr-abl--history--United States. 4. Genetic Therapy--history--United States. QZ 11 AA1]
616.99’419042--dc23
2012047686
ISBN 978-1-61519-067-6
Ebook ISBN 978-1-61519-165-9
Cover design by Jason Gabbert
Cover photograph © 2006 Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine
Author photograph © Meredith Heuer
Text design by Pauline Neuwirth, Neuwirth & Associates, Inc.
Manufactured in the United States of America
Distributed by Workman Publishing Company, Inc.
Distributed simultaneously in Canada by Thomas Allen & Son Ltd.
First published May 2013
10 9 8 7 6 5 4 3 2 1
To Evangelos and my other guiding lights
CONTENTS
Author’s Note
Foreword by Robert A. Weinberg, PhD
Prelude: Down to the Bone, February 2012
Part I: The Chromosome and the Disease, 1959–1990
1. The First Clue
2. Three Hundred Words
3. Investigating a Chicken Virus
4. Right Number, Wrong Place
5. The Surprising Source of the Chicken Cancer Gene
6. Consummate Instigators
7. Where the Kinase Hangs the Keys
8. A Chemical Amputation
9. Stripping Away the Fur and the Fat
10. A Funny New Protein
11. The First Sign of a Human Cancer Gene
12. Spelling Out the Translocation
13. “That Word Is Oncogenes”
Part II: Rational Design, 1983–1998
14. Becoming a Doctor, and Then a Scientist
15. Turning a Protein into a Drug Target
16. A Machine with a Virus for a Motor
17. Plucking the Low-Hanging Fruit
18. A Drug in Search of a Disease
19. Two Endings
20. Getting Out of Boston
21. Killing Cells
22. Gain and Loss
23. “Not Over My Dead Body Will This Compound Go into Man”
Part III: Human Trials, 1998–2001
24. The Quickest Answer
25. Getting to 200 Milligrams
26. The One Thing They Didn’t Have
27. Buzz in the Chat Rooms
28. Saving Their Own Lives
29. A Response Rate of One Hundred Percent
30. Good Stressful
31. Putting It in Writing
32. A Truckload of Data
33. The Fathers of Victory
Part IV: Aftermath
34. A Price to Pay
35. Showing a Weakness
36. The First Five Years
37. The Second Generation
38. A Gleevec for Every Cancer
Epilogue: Survival Time
PLATES
Glossary
References
Acknowledgments
Index
Photo Credits
About the Auth
or
AUTHOR’S NOTE
This book draws extensively from interviews I conducted with those who lived this story. Unless otherwise indicated, all quotes herein are from those interviews, which took place in 2012 or, in the case of a few scientists, 2007. Where quotes are taken from other material, the original source is noted.
Also, chronic myeloid leukemia (CML), the blood cancer that is this book’s focus, is alternately referred to as chronic myelogenous leukemia. I elected to refer to chronic myeloid leukemia, except when I quote from interviews or previously published material in which “myelogenous” was used; in these instances, “myelogenous” has been retained.—JW
FOREWORD
BY ROBERT A. WEINBERG, PHD
A widespread illusion is that cancer is a disease of modernity, an artifact of pollution and bad diet and myriad other factors associated with a modern lifestyle. The truth is quite different: The disease of cancer threatens all multicellular life with greater or lesser frequency. In the case of our own species, cancer incidence has exploded because we now live long enough to develop a disease—much like Alzheimer’s—that largely strikes the aged.
Until recently, we did not know how and why the disease arose, and yet, in spite of this, we developed the means to treat some—but hardly all—forms of the disease. The use of chemotherapy and radiation has had a remarkable effect in treating some cancers and almost no effect on others. By the early 1970s, however, it was already clear that these cytotoxic therapies had yielded almost as much benefit as they possibly could; that is, they had exhausted their potential for making major inroads into reducing cancer-associated mortality. Those looking over the scientific horizon concluded that new ways of treating the disease were required.
The thinking of those interested in such innovations in cancer treatment focused on how the disease was being caused. If only one could understand the defects within cancer cells, they reasoned, novel ways of treating the disease would surely emerge. This article of faith gained currency with the discoveries in the second half of the 1970s that distinct cancer-causing genes could be found within cancer cells. The genes—soon called oncogenes—appeared to be the motive forces behind the runaway proliferation of many types of human cancer cells. By attacking these genes (and more specifically, the proteins that they produced), highly targeted, extremely effective therapies could be developed, or so the thinking went.
The proponents of this new approach to dealing with cancer portrayed their strategy as a means of developing anticancer drugs rationally, by focusing on specific molecular defects within cancer cells. They contrasted this new way of treating cancer with the traditional strategies involving cytotoxic treatments, which were portrayed as blunt, crude instruments that had been used with limited success for the previous several decades. The latter therapies had been developed without any knowledge whatsoever of why cancer cells behaved aberrantly. For the first time, the prospect was bright; by attacking malfunctioning proteins within cancer cells, tumors as a whole could be brought to their knees.
By the early 1980s, the research into the molecular origins of cancer began an explosive growth, and by the end of the century we had amassed a truly extraordinary body of detailed information on why cancer cells proliferate abnormally. Translating these results into novel treatments, however, has not come so easily. There have been the usual scientific obstacles of developing drugs that could strike the cancer cells with great specificity, selectively killing those cells while leaving their normal counterparts relatively unaffected. Such selectivity in targeting cancer cells is rarely absolute; almost always, side-effect toxicities attend even the most successful targeted therapies. Then there were the economic considerations, specifically, whether the rapidly growing cost of developing novel anticancer therapeutics could ever be recouped through clinical drug treatments.
The Philadelphia Chromosome focuses on what is widely viewed (at least among those of us in cancer research and treatment) as the “poster child” of rational drug development. The story that this book relates vindicates those who dreamed that one day cancers could be treated through rationally designed drugs—and in fact remains the major success story to this day. It has been followed, disappointingly, by few comparable success stories. It is also a story that almost didn’t happen.
The development of Gleevec might never have occurred because those keeping the books in the drug company that incubated this drug argued that the disease was too uncommon to justify major investments in its development. They said that the costs of drug development would never be compensated by sales. Fortunately they did not prevail, and the prophets of rational drug design pushed ahead and generated a truly spectacular therapeutic agent.
By following the step-by-step process launched by the discovery of an aberrant chromosome in the leukemic cells of those suffering from chronic myeloid leukemia, it becomes possible to see how truly challenging anticancer drug development can be, both at the preclinical level (i.e., in the laboratory) and in the clinic itself. The diagnosis of CML was once a death sentence because of its almost-inevitable progression after several years to the “blast crisis” that signals the end of life for patients. These days, CML diagnosed early can become a chronic disease—never cured, strickly speaking, but kept in check so effectively that patients often forget they harbor small nests of leukemic cells in their marrow—cells that are kept penned up by the miracle drug that they regularly take.
Why has Gleevec been so spectacularly successful in treating CML, while analogous drugs treating other forms of cancer have had mixed results, often eliciting short-term responses followed by drug-resistant clinical relapses? The answers lie in part in the fortuitous choice of treating a disease that has not yet become aggressive, stopping it in its tracks, in contrast to most other forms of cancer, which are frequently diagnosed late in their natural progression and thus endowed with the means of evading the therapies dispatched to eliminate them. This book makes good reading for those interested in the work of the heroes who pushed this drug forward to its truly brilliant successes.
• • •
Robert A. Weinberg, PhD, is a Daniel K. Ludwig Professor for Cancer Research at MIT, an American Cancer Society Research Professor, and a member of the US National Academy of Sciences. He is an internationally recognized authority on the genetic basis of human cancer. Credited with the discovery of the first human cancer-causing gene as well as the first tumor suppressor gene, he was awarded the National Medal of Science in 1997 and the Wolf Prize in Medicine in 2004. He is the author or editor of five books and more than 325 articles.
PRELUDE
Down to the Bone
February 2012
• • •
Gary Eichner sat in a chair backed up against a wall. Across the room, his nurse was half hidden by a computer. She scrolled through his medical chart on a monitor he couldn’t see, typing his responses to her questions. He answered and smiled as if he were just fine, as though that would somehow make it so. He kept his worry concealed, silently wondering what the next hour would reveal about the disease that had so suddenly overtaken his life. Fear permeated his every thought.
The nurse ran through the litany of side effects that he might be experiencing from the leukemia medication he’d recently begun to take. “Any chest pain?” she asked. “Heart problems? Any swelling in your ankles? Any problems with nausea?”
Eichner’s blanket “no” was tempered only by his description of what happened when he took the drug on an empty stomach. “It’s massive cramping, massive pain in the stomach,” he told the nurse. “It’s just like the worst thing you’ve ever had.”
The nurse knew that Eichner really had no idea of the worst thing someone with his type of leukemia could have. Few patients with Eichner’s disease today will ever know that kind of pain.
But if the nurse was thinking anything of the sort, she kept it to herself. After all, her patient was about to have a large, hollow needle inserted into his bone
so that his doctor could extract a sample of his marrow. Having witnessed countless such procedures during the twelve years she’d been a nurse to patients taking the drug, she knew how much was riding on this biopsy, and she knew that Eichner, age 43, was well aware that his life was at stake.
If anyone could set him at ease about that, it was his doctor, Brian Druker. “All I care about is that you’re making some progress,” Druker told his patient, who had come to Druker’s clinic in Portland, Oregon, for a bone marrow biopsy. The procedure would reveal whether the medicine—a pill he’d been taking daily for six months—was tackling the leukemia that had invaded his body. Eichner had chronic myeloid leukemia, or CML, a cancer of the white blood cells that, though slow growing, could be fatal. “I will be happy if you’re eighteen out of twenty.” Eichner nodded his understanding, his jittery foot the only sign of his nervousness.
For Eichner, those numbers were part of the new language he’d learned since his diagnosis in the summer of 2011. As with so many cancer diagnoses, the education began suddenly and unexpectedly. After a day or so of sharp, excruciating kidney pain, Eichner, a single parent of a teenage boy, drove himself to the emergency room at his local hospital in Olympia, Washington, where he’d been living at the time. His sister-in-law, a trauma flight nurse, had told him she thought he had kidney stones, so Eichner was expecting to be admitted for a standard, albeit painful, procedure. But when several doctors walked into his hospital room together, he knew something wasn’t right. “You don’t have kidney stones,” they told him. “You’ve got what we believe is leukemia.”
A blood test soon revealed that Eichner, in otherwise perfect health, had CML. The excess number of white blood cells contained in the sample confirmed that much. The doctors explained that the stabbing pain he’d thought came from his kidneys probably was from his spleen, enlarged by the high concentration of leukemia cells within. Although the slow-moving nature of the disease meant he wasn’t in immediate danger, there wasn’t any time to lose. For the best chance at long-term survival, he needed to start treatment right away.
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