abl oncogene, 78
cellular origin, 44, 58
converted by environmental factors, 50
Kipnis on, 91, 97
oncogenic retroviruses, 30
online chat, phase I patients, 199
online petition, 206, 208
Oregon Health and Science University (OHSU)
Druker and, 136, 218, 238
Knight Cancer Institute, 246
Orem, Judy, 190, 218, 221, 244, 271
Orphan Drug Act (ODA) (1983), 229
orphan drugs, 229, 254
overexpression, 106
P
p38 (protein), 266
Painter, Theophilus, 35
Parker, Peter, 48
Patent and Trademark Law Amendments Act (Bayh-Dole Act), 263
patent expiration, 258, 265
Pazdur, Richard, 234
PDGFR (platelet-derived growth factor receptor), 106, 114, 118, 119, 126, 138, 143, 163, 247
personal genome sequencing, 261, 265, 269
pharmaceutical companies, 131
pharmaceutical industry, mergers in mid-1990s, 156
phase I clinical trial (of CGP-57148B/STI-571), 146, 154, 171, 175
blast crisis patients, 176, 178, 196, 198
commitment of study participants, 182
costs of, 178
cytogenetic response, 183, 211
drug delivery, 179
early stage CML, 177, 178, 196
FDA approval announcement mention, 235
hematologic response, 183, 211
length of trial, 180
minimum/maximum drug level, 184
objective, 178, 188
organization of study, 181
presentation of results to ASH (1999), 208, 210, 213
sites, 181
starting dose, 183
phase I patients
commitment of, 182
online chats and message boards, 199
phase II clinical trial (of STI-571), 196, 198, 201, 215, 216
for accelerated disease patients, 216, 226
for blast crisis CML, 204, 216, 218, 226, 249
for chronic-stage disease, 204, 210, 216, 218, 227
drug production expedited, 209, 213
drug resistance, 249
drug shortage for, 201, 202, 203, 205, 208, 209, 217
FDA approval announcement mention, 235
phase III clinical trial (of STI-571) (IRIS), 201, 219, 233, 247, 253, 255
2-phenylaminopyrimidine, 126
Philadelphia chromosome (Ph1)
in 1960s, 22, 25
abl gene moved to, 84
about, 5, 79
Bcr/Abl tyrosine kinase and, 106
chromosome 9 and, 84, 85, 88
chronic myeloid leukemia and, 93
confirmation of existence, 21
as deletion, 22, 38
discovery, 15
publication, 21
Rowley’s work, 38
as spontaneous mutation, 191
as translocation, 39, 84, 85, 87
phorbol esters, 106
phosphates, signal transduction and, 47, 51
phosphonates, 107
phosphorylation, 54, 55, 89
of bcr/abl fusion gene, 87
of tyrosine, 102
phosphotyrosine, antibody against, 102, 116
PI3K, 266
Picton, Colin, 48
Piro, Lawrence, 90
PKC (protein kinase C), 106, 110, 114, 118, 119, 122, 124, 126
poliovirus, tyrosine and, 73
Pollack, Andrew, 267
polymerase chain reaction, 255, 256
polyomavirus, 53, 73, 99, 129
ponatinib, 260
poverty, CML treatment and, 264
prednisolone, 61
preleukemia, 37
proprietary name, 231, 232
protein kinase, 46
protein phosphorylation, 47, 89
proteins, 29, 45
“The Proteins of Oncogenes” (Hunter), 89
proto-oncogenes, 44, 50, 77, 88
abl oncogene, 78
encoding kinases, 89
purging, 145
Q
quercetin, 124
quinacrine mustard, 37
R
radioactive src probe, 43, 60
ras genes, 50
rational drug design, 108, 112, 266
reciprocal translocation, 39
recombinant DNA, 49, 50, 76, 81, 82, 88
Reinhardt, Jörg, 204, 215
relapse, 197, 257
resistance (drugs). See drug resistance
retroviral oncogenes, cellular origin of, 44
retroviruses, 30, 44, 78
reverse transcriptase, 30, 64, 65
RNA, 29
RNA viruses, 29
capture genes from host, 60, 78
containing all genes needed for replication, 59
replication, 64
Roberts, Tom
career, 97
research, 99, 100, 102, 115
Roche Pharmaceuticals, 104
Rockefeller Institute for Medical Research, 25
Rockefeller University, 25
Romine, Bud, 158, 181, 182, 184, 193, 195, 215, 271
Roscoe, May Belle, 190
Rosenberg, Naomi
about, 69, 71, 77, 88, 99
career, 65
research, 66, 72, 75, 113
Rous, Peyton
about, 25
chicken cancerous tumor, 26, 88
Rous sarcoma virus (RSV), 27, 29, 64, 88
temperature-sensitive mutations, 31, 40
Rowley, Janet
about, 58, 183
award, 245
career, 36
research, 37, 68, 81
Rubin, Harry, 28, 31
S
Sandostatin, 167
Sandoz, 120, 131, 139, 156
Sawyers, Charles
about, 150, 152, 200, 218
award, 238
research, 181, 182, 187, 188, 196, 197, 198, 248, 252, 257
Scher, Chuck, 67
Schering-Plough, 105
second-generation tyrosine kinase inhibitors, 258, 261, 268
serine, 54
Shannon, James, 209
Shoemaker, Chuck, 77
signal cascade, 47, 51
signal transduction, 47, 100
signaling pathways
inhibiting with drugs, 115
triggered by bcr/abl fusion gene, 87
skin cancer, 106
Slater, Robert, 237
Sprycel (dasatinib), 259
src gene, 31, 40, 64
original source of, 41, 49, 75, 88, 98
protein product, 45
Src kinase, 64, 74
src probe, 43, 60
Src protein, 40, 41, 45, 74
staurosporine, 122, 124
STI-571 (Novartis), 157
accelerated approval, 214, 215, 230
animal studies, 158, 170
brand name, 230
commercial production, 216
drug shortage for phase II trial, 201, 202, 203, 205, 208, 209, 217
duration of treatment in patients, 166, 169
economics of development, 214
“expanded access” trial, 220, 227
fast-track designation, 214, 215, 230
FDA approval, 232, 234
FDA review, 214, 227, 230
generic name, 230
investigational new drug (IND) application, 154, 165, 169
lack of response to, 197, 198
name of and FDA, 230
orphan drug status granted, 229
phase I clinical trial, 171, 175
phase II clinical trial, 196, 198, 201, 215, 216
phase III clinical trial (IRIS), 201, 219, 233, 247, 253, 255
priority review status, 230
relapse, 197, 257
side effects, 188, 194, 211, 227, 248
success stories in STI Gazette, 217, 222
supply of drug for phase II trials, 201, 202, 203, 205, 208, 209, 217
toxicity concerns, 160, 163, 164, 169, 171, 179, 211, 233
See also CGP-57148B
STI Gazette (newsletter), 185, 217, 221, 232, 270
Stiles, Chuck, 115, 116, 163
stomach cancer, 247, 266
sunitinib, 266
survival data, 267
swanson, Robert, 50
T
T-cell cancer, 61
T-cell leukemia, 76
T cells, 60, 61
T315 mutation, 260
Talpaz, Moshe, 151, 181, 187, 188, 197, 200
tamoxifen, 132, 235
targeted therapy, 109, 266, 267
Tasigna (nilotinib), 259
Tay-Sachs disease, 82
technology transfer, Bayh-Dole Act, 263
Temin, Howard, 28, 30, 58, 64, 65
ten-year survival data, 267
testicular cancer, 97
testing
combinations of experimental drugs, 264
exploration of new ways, 262
Gleevec development, 113, 114, 117, 138, 152
thalidomide babies, 162
Thompson, Tommy, 234, 247
threonine, 54
Tjio, Joe Hin, 35, 144
TKL family, 266
transfer agreements, 263
transformation system, 67, 68, 69, 71, 89
transforming viruses, 30
“translational research,” 100
translocation, 39, 81, 84, 85, 87
Traxler, Peter, 110, 123, 127, 128
tumor sequencing, 261, 265
tyrosine, 55, 58, 73, 102
tyrosine kinase
blocking, 102
early research, 55, 73, 74, 75, 78, 86, 88
tyrosine kinase inhibitors
new drug development, 265
for non-responders, 260
sales projections, 266
second-generation, 258, 261, 268
See also Gleevec; kinase inhibition
tyrosine kinases, study outside of the cell, 115
tyrosine phosphorylation, 55
U
upfront resistance, 250, 251
V
v-erbB protein, 106
v-sis protein, 106
Varmus, Harold, 42, 43, 44, 68, 72, 75, 77, 78, 88, 98, 99
Vasella, Daniel
about, 167, 213, 264
academia-industry collaborations, 262
clinical trials, 168, 169
drug supply for phase II, 203
FDA approval announcement, 234, 236
Magic Cancer Bullet, 237
Matter and, 167
McNamara online petition, 206
on Novartis drug cost assistance program, 244
patent expiration, 258
Verma, Inder, 77
viruses
cancer and, 27, 30, 58, 88
recombinant DNA, 49, 50, 76, 81, 82, 88
transformation system, 67, 68, 69, 71, 89
types, 28
Vogelstein, Bert, 265
W
Watson, James, 158
Weinberg, Robert A., xiii, 98, 115
white blood cells, 61
in leukemia patients, 19
Wigler, Michael, 98
Wilkins, Maurice, 158
Witte, Owen
about, 74, 79, 81, 89, 152
career, 69, 70, 78, 79
research, 69, 73, 75, 78, 85, 86, 88, 89, 102, 112, 118, 267
World Wide Web, phase I patient chats, 199
X
x-ray crystallography, 251
Z
Zimmermann, Jürg
about, 148, 249
career, 121, 140
early life, 120
opinions and quotes, 108, 109, 110, 147, 162
research, 123, 124, 163, 182, 251, 252
PHOTO CREDITS
1. Peter Nowell, MD, and David Hungerford: Photograph taken by Larry Keighley, courtesy of Alice Hungerford.
2, 3. Microscope photographs of the Philadelphia chromosome: Photograph courtesy of Alice Hungerford.
4. Naomi Rosenberg’s cell cultures: Photograph courtesy of Naomi Rosenberg.
5. Barred Plymouth Rock hen: 1910, Rockefeller University Press. Originally published in The Journal of Experimental Medicine. 12:696–705.
6. Bone marrow biopsy: Republished with permission of the American Society for Clinical Investigation, from “Applying the Discovery of the Philadelphia chromosome,” Daniel W. Sherbenou and Brian J. Druker, Journal of Clinical Investigation, Volume 117, Issue 8, 2007; permission conveyed through Copyright Clearance Center, Inc.
7. src probe diagram: Illustration © Molly Feuer, Feuer Illustration. Text by the author.
8. Janet D. Rowley, MD: Photograph courtesy of Janet D. Rowley.
9. Philadelphia chromosome translocation: © 2007 Terese Winslow, U.S. Govt. has certain rights.
10. Karyotype with Philadelphia chromosome: From the Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine. Image courtesy of Peter C. Nowell, MD, and Kristin Nowell.
11. From Philadelphia chromosome to CML diagram: Illustration © Molly Feuer, Feuer Illustration. Text by the author.
12, 13. Hematologic and cytogenetic (FISH) responses to CML: Republished with permission of the American Society for Clinical Investigation, from “Applying the Discovery of the Philadelphia chromosome,” Daniel W. Sherbenou and Brian J. Druker, Journal of Clinical Investigation, Volume 117, Issue 8, 2007; permission conveyed through Copyright Clearance Center, Inc.
14. Jürg Zimmermann: Photograph courtesy of Jürg Zimmermann.
15. Elisabeth Buchdunger: Photograph courtesy of Elisabeth Buchdunger.
16. Warren Alpert Prize award ceremony: Photograph courtesy of The Warren Alpert Foundation.
17. Brian Druker, MD, and LaDonna Lopossa: Photograph by Michael McDermott and courtesy of Oregon Health & Science University.
18. Gleevec pill: Photograph courtesy of Novartis.
19. 50th anniversary group photo: Photograph courtesy of Fox Chase Cancer Center.
20. Gary Eichner and son: Photograph courtesy of Gary Eichner.
21. Novartis ad featuring Suzan McNamara: © Novartis.
ABOUT THE AUTHOR
JESSICA WAPNER is a freelance science writer focused mainly on health care and medicine. Her work has appeared in publications including Scientific American, Slate, The New York Times, theatlantic.com, New York, Science, Nature Medicine, the Ecologist, the Scientist, and Psychology Today. Her writing on cancer research and treatment has also appeared in the patient-focused magazines CR and Cure, and she has been a frequent contributor to the industry publication Oncology Business Review. She lives with her family in Beacon, New York.
www.JessicaWapner.com
* Following scientific convention, genes in this book are denoted in lowercase italics (hence src), and proteins are capitalized and in plain font (hence Src).
† Bishop, who, together with lab member Art Levinson, had likewise been searching for the src gene product, also found the kinase. Their paper was published three months later. Credit for the discovery goes to Erikson and Collett.
‡ The technology behind recombinant DNA is credited to Herb Boyer, then at the University of California–San Francisco, and Stanley Cohen, then at Stanford University. In 1976, Boyer and venture capitalist Robert Swanson founded Genentech, the first biotech company, with the goal of using recombinant DNA to develop new drugs. The company’s first product, human insulin, was cloned in 1978. The pharmaceutical company Eli Lilly licensed the drug, which was approved in 1982.
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The Philadelphia Chromosome Page 33
