Dr.

Folkman's War: Angiogenesis and the Struggle to

Defeat Cancer

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ALSO BY ROBERT COOKE

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DR. FOLKMAN'S WAR
DR. FOLKMAN' S
WAR
Angiogenesis and the

Struggle to Defeat Cancer

ROBERT COOKE

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Random House Xcir York
 Copyright © 2001 by Robert Cooke

All rights reserved under International and Pan-American Copyright

Conventions. Published in the United States by Random House, Inc.,

New York, and simultaneously in Canada by Random House of

Canada Limited, Toronto.

Random House and colophon are registered trademarks

of Random House, Inc.

Library of Congress Cataloging-in-Publication Data

Cooke, Robert
Dr. Folkman's War: Angiogenesis and the struggle to defeat
cancer/Robert Cooke.
p. cm.
ISBN 0-375-50244-0
1. Neovascularization inhibitors —Therapeutic use. 2. Cancer
Chemotherapy. 3. Folkman, M. Judah. 4. Cancer —Research.
I. Title.

RC271.N46C66 2000
616.99'4061 —dc21 00-34165

Random House website address: www.atrandom.com

Printed in the United States of America on acid-free paper
24689753
First Edition
To my wife, Sue C. Cooke,

who loves greatly,

cares deeply, and

makes all things possible

 Foreword

C. Everett Koop, M.D., Sc.D

IN AN INSPIRED MOVE by a smart university, Harvard appointed Judah

Folkman surgeon-in-chief of the Boston Children's Hospital despite his lack

of specific training in the surgery of children —an established specialty with

its own rigorous board of certification. Harvard chose Dr. Folkman for his po-
tential, not his past performance in pediatric surgery.
I have no idea whether Harvard knew they were appointing a rare bird in
surgery — the surgeon scientist. Harvard sent Judah Folkman to me at the

Children's Hospital of Philadelphia for an abbreviated training period in pe-

diatric surgery. I'm told it is the first time Harvard sent a full professor any-
where for training. The six-month period we were together was unusually
stimulating. Surgeons get in the habit of doing things a certain way because
"it works," but Judah never let me do anything without a reason that I could
defend.
He had powers of observation that were unusual, and I enjoyed being
around him and trying to show him more.
Two anecdotes illustrate the depth of Judah's powers of observation. Re-
member that Judah Folkman was a well-trained surgeon but had no experi-
ence handling the very delicate tissues of young children. At the end of the
first week that we worked together, I was about to bring down the unde-
scended testicles of a small baby, a wonderful teaching opportunity: I would
do one side, explaining every step I took, and then coach Judah as he did the
other side. I finished my side in a little longer than the seventeen minutes that
it usually took because I was explaining as much as I thought was necessary.
About an hour and a quarter after Judah started his side he was in trouble: The
hernial sac was in fragments, real skill was going to be needed to repair the sit-

uation, and Judah was unbelievably frustrated. Together, we made things

x • FOREWORD
right and closed his side, about one hour and forty-five minutes after he had
started. I did the best I could to reassure him, telling him that in one fell

swoop he had learned the difference between delicate pediatric tissues and the
tougher ones of adults and that the experience, although somewhat humiliat-
ing, would stand him in good stead.

The next morning I met him in the hallway when he arrived early to make
rounds. He rushed up to me, all smiles, and said, "Fingernails! Fingernails!"

I said, "What do you mean?" He replied, "Fingernails! You have fingernails

and I don't. Your technique is largely dependent upon your ability to use your
left thumbnail to steady things against your left forefinger, while you dissect
the delicate tissues attached to the parts of spermatic cord you have mobi-

lized." He was absolutely right, but I had never realized how important my
nondominant hand's thumbnail was to my surgical prowess. I'm told that

when Judah got back to Boston's Children's Hospital, he made his residents

grow a thumbnail on their nondominant hand.

Later, after Judah had gone back to Boston and was settled into his new
job, he invited me to give a lecture at the Boston City Hospital. I chose to talk

about my experiences with the difficult surgery on malignant tumors in chil-

dren, and to illustrate it with some dramatic slides. One of the slides showed
a child lying in the operating room with his abdomen stitched closed after a

procedure. On his abdomen and chest was the blood clot I had removed from
the renal vein, the vein that goes from the kidney into the vena cava, the major
vessel of the abdomen carrying blood back to the heart. The blood clot in
question had extended about an inch and a half down the renal vein, taken a

sharp left turn up the vena cava through the chest and then a left U-shaped
turn into the right atrium, the upper chamber of the heart. The clot was com-
posed of blood and tumor tissue. The purpose of including it in my lecture

was simply to show that you can remove even such a huge clot containing

tumor through an incision in the vena cava, get the child off the table alive,

and, indeed, see him recover completely.

The next slide I showed was a microscopic one taken through the tip of the
clot in the chamber of the heart. I said, "This is just to show you that this was
a metastasis in the making because here you see, in the tip of the thrombus,
Wilms' tumor [a malignant tumor of the kidney that occurs in children]." I

had the slide on the screen for perhaps ten seconds when Judah yelled, "Stop,
stop!" I le then showed the audience that right in the tip of the clot all that dis-

tance from the kidney was a tumor trying to survive, and right in the center

you could see a capillary. This was, of course, Judah's mind, off on its own
 FOREWORD • xi

where no one else had been, observing the angiogenesis factor, the then-
mysterious force that called that blood vessel into the tumor so far from its

parent in the kidney.

It wasn't long after Judah began his career in Boston that he discovered the
importance of blood vessels in pathological processes and began the research
that led him to the angiogenesis factor, the factor that stimulates the growth of

blood vessels in usual and unusual places. Some seminal research projects take
a relatively short time —such as Crick's and Watson's discovery of the double
helix, which took about two years. Other projects, like Perutz's work on he-
moglobin, can take a quarter of a century. That kind of research takes the stam-

ina and the commitment of a long-distance runner — the ability to stay the

course and persevere. That is and was the modus operandi of Judah Folkman,
as he persisted over the years, learning more and more about angiogenesis and
its antagonists.

The outstanding quality of Judah's research is that it has such broad ap-
plicability. So far, his research has found applications in twenty-six diseases as

varied as cancer, diabetic retinopathy, macular degeneration, psoriasis, arthri-

tis, and endometriosis. Ordinarily, researchers working in any of these fields

do not communicate with each other. They do dig parallel trenches, as it were,
and like train tracks they go in the same direction but never meet. The angio-
genesis and antiangiogenesis factors research has impact across disciplines.

Specialized researchers did not know that they were dealing with the same
molecule. Judah connected the parallel trenches, and the resultant cross-
fertilization has led to discoveries that are important to oncologists, ophthal-
mologists, gynecologists, dermatologists, and many others.

Dr. Folkman's discoveries did not meet with instant approval and acclaim;
there were many doubters over the years. In the 1970s, laboratory scientists
didn't believe any of it. Angiogenesis was not something to be taken seriously:
Tumors didn't call in blood vessels, period. In the 1980s, the critics began to

believe in the theory of angiogenesis, but not that specific molecules were in-

volved. Then textbooks began to include angiogenesis and it was considered

to be a well-established phenomenon; the critics' objections were hushed for
good in 1989. In the 1990s, the criticisms came chiefly from the clinical side,

and the pharmaceutical companies didn't want anything to do with angiogen-

esis. In the end, of course, Judah Folkman's beautiful idea has triumphed over

the doubters. A few still persist, but their time will come.
 Acknowledgments

IT IS HARDLY POSSIBLE to thank Dr. Judah Folkman enough for spar-

ing his time, insight, humor, and depth of knowledge to make the preparation

of this book possible. As Dr. C. Everett Koop said during one interview, any-
one who spends much time with Judah Folkman comes away changed — for

the better. That is true.

Deep appreciation must also be expressed for the dedication and skill of
writer/editor Richard Firstman, who signed on in mid-book to help me fash-

ion a loosely organized project into a coherent story that I think readers will
enjoy. He was masterly at asking the right questions, getting me to fill in

blanks, and putting flesh on bare bones that were rattling badly. Rick First-
man's ability to see the big, overall picture while I was mired in technical de-

tail was especially valuable. Thanks, too, for his patience and for his ability to

beat my stumbling words into decent shape.

There are, of course, many others who deserve thanks, and Paula Folkman
ranks high among them for her patience, good humor, and steadfastness. Also,
thanks to Judah Folkman's willing staff at Children's Hospital in Boston, es-
pecially office experts Polly Breen, Wendy Foss, and Emy Chen, who field so

many calls with unfailing grace and empathy. Most of the others who deserve
thanks are mentioned in the text, but I must express appreciation for Rakesh
Jain, Pat D'Amore, and Susan Connors and others who were involved in var-

ious parts of the angiogenesis research program.

In addition, thanks must be expressed for the time and effort given to me
by David Cheresh at the Scripps Research Institute; his patient Barry Riccio
and Barry's wife, Kathryn Anthony; former American Cancer Society em-
ployee Leo Allard; the ACS media representative Joanne Schellenbach; Dr.
Gerald Soff at Northwestern University Medical School in Chicago; David
\n • W.KNOWLEDGMENTS
Anderson at the California Institute of Technology; Dr. Richard Klausner, di-

rector of the National Cancer Institute; Don Gibbons and his staff at the Har-
vard Medical School News Office; Bess Andrews at Children's Hospital in
Boston; and my two dedicated transcribers, Linda Goetzfried and Jean Fes-
senden. Special thanks, too, must go to Faith Hamlin, my agent at Sanford J.

Greenburger Associates in New York, whose ability to nurse an author

through the creation process was invaluable.
Thanks also to the able team at Random House who were central to getting
this book published. They include president and publisher Ann Godoff,
Mary Bahr, Amy Edelman, Sunshine Lucas, Kate Niedzwiecki, Carol Schnei-
der, Tom Perry, Sally Marvin, Tracy Howell, Tracy Pattison, Linda Pennell,
Martha Schwartz, Andy Carpenter, Richard Elman, and Barbara Bachman.
Special thanks to senior editor Scott Moyers, whose enthusiasm and editorial

skills improved the book immeasurably.

Gratitude is also due to my employer, Newsday Inc., and my editors there
for helping me finagle enough time and energy to pursue this project. Because
of their flexibility and understanding, it was possible to make several dozen
trips to Boston and back for crucial interviews and important events, some-
times on short notice.
Saying thank you is hardly enough, though, for the care and support I con-
tinue to receive from good friends in and around Sudbury, Massachusetts,

whose deep friendship will always be cherished. These beautiful people in-
clude Ted and Jan Carvalho, Floyd and Marge Stiles, Ed and Nancy Ross, Bob
and Alice Vannerson, and in Vermont, Bill and Barbara McBride. Such
friends are irreplaceable.
 Contents

Foreword by C. Everett Koop / ix

Acknowledgments / xiii

PART ONE / 1

PART TWO / 107

PART THREE / 219

Index / )}i
 Chapter One

IT WAS A TANTALIZING idea that Judah Folkman had nurtured for

nearly four decades —he had hatched it, worked it, published it, defended it,

romanced it. He had withstood the ridicule of his peers. He had fought bat-
tles of medical and scientific politics. And he had endured, seemingly ob-
sessed, never straying from the ideas in his head, the conviction in his heart,

and the truth he saw in his laboratory. That was where the real battles were
waged, where Folkman had been trying for nearly forty years to read and un-
derstand Nature's book, page by page. Now the time had come to see what it

all amounted to. The answers were starting to trickle in from medical wards
around the country, and there was little more for Folkman to do than wait,

and hope.
At the core was a simple notion that had gradually matured in Folk-
man's mind ever since that day in 1961 when he was noodling in a navy lab in
Bethesda, Maryland, a twenty-eight-year-old draftee trying to make cells
grow under artificial conditions. That was when he'd first noticed a strange
thing about tumors: They wouldn't grow unless they first recruited their own
blood vessels. Over time he convinced himself that there had to be some way
to block the growth of those blood vessels. To starve the tumor to death —and
save the patient.

So Folkman had been trying to conquer cancer for nearly four decades
when, in the waning days of the twentieth century, the first patients began to

be infused with the natural drugs that had come from his long campaign. The
new compounds had worked marvelously in mice
—"We've never lost a

mouse yet," Folkman liked to say —and now they were being given the first

crucial tests in men and women. Three clinical trials were under way to test

one of the potent substances, endostatin, that had been discovered in Folk-
4 • ROBERT COOKE
man's laboratory. And as many as two hundred biotechnology companies,
some large and others tiny, were exploring the once-ridiculed field that Folk-
man had years before named "angiogenesis," meaning the growth of the
blood vessels de novo needed to support tumor growth.
In Boston, where Folkman had lived, studied, and worked since leaving
Ohio behind in 1953, the volunteers trooped to the Dana-Farber Cancer In-
stitute for their daily infusions of the possible wonder drug. The infusion cen-
ter was on the ground floor, equipped with a collection of beds, some of which
were fashioned after chairs, designed for patients who could take their medi-
cine sitting up. Each would take his or her place, and the dose would then be
thawed. Endostatin was a precious commodity that couldn't be wasted — the
first one-kilogram batch was said to be worth seven million dollars — so it was
never thawed before the patient actually arrived, in case the patient didn't
show up. But they always did. These were people facing terminal cancer, des-

perate for the cure and very relieved to find that this drug, unlike the standard

chemotherapy they had received, did not make them awfully sick. Of course,
they hoped the treatments would also be different in a much more important
way: Chemotherapy had not worked. That's why they were here. The infusion
process, during which the drug was given through an IV line, lasted twenty
minutes. Then the patients would leave, returning the same time the next day,

Saturdays and Sundays included.

Would the new treatment live up to its billing, actually erase tumors with-
out dangerous side effects? Would patients who had been given little or no

chance of survival emerge unscathed, as if touched by magic? No one could

tell —but everyone was watching. Although the first phase of the trials was
only meant to test for signs of toxicity, those involved could not resist the nat-
ural impulse to peek beyond the government-enforced protocols, hoping for

signs, even the barest hint, of efficacy. The doctors running the trials, gagged
by their institutions, refused to utter a public word. But the rumors were fly-

ing. The doctors talked sub rosa, and so did the nurses and interns who were
close to the trials. Word got around the biomedical grapevine that at Dana-
Farber and both of the other experiment centers conducting the trials in

Texas and Wisconsin some patients' tumors had stopped growing. One man,
it was said, had experienced remarkable progress. As one insider put it, the

mystery man's cancer, both the primary tumor and its dangerous metastases,
had been "galloping." But since he began getting endostatin — in only small

doses during the toxicity phase of the trial — his tumors had shrunk by half.

One patient was just one patient, but it was an encouraging start.