Hughes, T. P., A. Hochhaus, S. Branford, M. C. Müller, J. S. Kaeda, L. Foroni, B. J. Druker, E. Guilhot, R. A. Larson, S. G. O’Brien, M. S. Rudoltz, M. Mone, E. Wehrle, V. Modur, J. M. Goldman, and J. P. Radich. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: An analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 116 (2010): 3758–3765.
Iba, H., T. Takeya, F. R. Cross, T. Hanafusa, and H. Hanafusa. Rous sarcoma virus variants that carry the cellular src gene instead of the viral src gene cannot transform chicken embryo fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 81 (1984): 4424–4428.
Kantarjian, H., S. O’Brien, G. Garcia-Manero, S. Faderl, F. Ravandi, E. Jabbour, J. Shan, and J. Cortes. Very long-term follow-up results of imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon alpha therapy. Cancer 118 (2012): 3116–3122.
Kantarjian, H., C. Sawyers, and A. Hochhaus et al.; International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. New England Journal of Medicine 346 (2002): 645–652.
Konopka, J. B., S. M. Watanabe, J. W. Singer, S. J. Collins, and O. N. Witte. Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration. Proceedings of the National Academy of Sciences of the United States of America 82 (1985): 1810–1814.
Konopka, J. B., S. M. Watanabe, and O. N. Witte. An alteration of the human c-abl protein in K562 leukemia cells unmasked associate tyrosine kinase activity. Cell 37 (1984): 1035–1042.
Lydon, N. B., B. Adams, J. F. Poschet, A. Gutzwiller, and A. Matter. An E. coli expression system for the rapid purification and characterization of a v-abl tyrosine protein kinase. Oncogene Research 5 (1990): 161–173.
Nishizuka, Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308 (1984): 693–698.
Nowell, P. C., and D. A. Hungerford. A minute chromosome in human chronic granulocytic leukemia. Science 132 (1960): 1497.
———. Chromosome studies on normal and leukemic human leukocytes. Journal of the National Cancer Institute. 25 (1960) : 85–109.
O’Brien, S. G., F. Guilhot, and R. A. Larson et al.; IRIS investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeoid leukemia. New England Journal of Medicine 348 (2003): 994–1004.
Rabstein, L. S., A. F. Gazdar, H. C. Chopra, and H. T. Abelson. Early morphological changes associated with infection by a murine nonthymic lymphatic tumor virus. Journal of the National Cancer Institute 46 (1971): 481–491.
Rowley, J. D. Chromosomal patterns in myelocytic leukemia. New England Journal of Medicine 289 (1973): 220–221.
———. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature 243 (1973): 290–293.
Sawyers, C. L., A. Hochhaus, and E. Feldman. Imatinib induces hematologic and cytogenetic responses in patients with chronic myeloid leukemia in myeloid blast crisis: Results of a phase II study. Blood 99 (2002): 3530–3539.
Schindler, T., W. Bornmann W, P. Pellicena, W. T. Miller, B. Clarkson, and J. Kuriyan. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289 (2000): 1938–1942.
Stam, K., N. Heisterkamp, G. Grosveld, A. de Klein, R. S. Verma, M. Coleman, H. Dosik, and J. Groffen. Evidence of a new chimeric bcr/c-abl mRNA in patients with chronic myelocytic leukemia and the Philadelphia chromosome. New England Journal of Medicine 313 (1985): 1429–1433.
Talpaz, M, R. T. Silver, and B. J. Druker et al. Imatinib induces durable hematologic responses and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study. Blood 99 (2002): 1928–1937.
Tamaoki T, H. Nomoto, I. Takahashi, Y. Kato, M. Morimoto, and F. Tomita. Staurosporine, a potent inhibitor of phospholipid/Ca++dependent protein kinase. Biochemical and Biophysical Research Communications 135 (1987): 397–402.
Whang, J., E. Frei III, J. H. Tjio, P. P. Carbone, and G. Brecher. The distribution of the Philadelphia chromosome in patients with chronic myelogenous leukemia. Blood 22 (1963): 664–673.
Witte, O. N. Involvement of the abl oncogene in human chronic myelogenous leukemia. Oncogenes and Cancer. Utrecht: Japan Society Press, 1987. S. A. Aaronson et al, editors. 143-149.
———. Role of the BCR-ABL oncogene in human leukemia. Cancer Research 53 (1993): 485–489.
Witte, O. N., A. Dasgupta, and D. Baltimore. Abelson murine leukemia virus protein is phosphorylated in vitro to form phosphotyrosine. Nature 283 (1980): 826–831.
Witte, O. N., N. E. Rosenberg, and D. Baltimore. Identification of a normal cellular protein cross-reactive to the major Abelson murine leukaemia virus gene product. Nature 281 (1979): 396–398.
Witte, O. N., N. Rosenberg, M. Paskind, A. Shields, and D. Baltimore. Identification of an Abelson murine leukemia virus-encoded protein present in transformed fibroblast and lymphoid cells. Proceedings of the National Academy of Sciences of the United States of America 75 (1978): 2488–2492.
Young, J. C., and O. N. Witte. Selective transformation of primitive lymphoid cells by the BCR/ABL oncogene expressed in long-term lymphoid or myeloid cultures. Molecular and Cellular Biology 8 (1988): 4079–4087.
Zimmermann, J., E. Buchdunger, H. Mett, T. Meyer, and N. B. Lydon. Potent and selective inhibitors of the Abl-kinase: Phenylamino-pyrimidine (PAP) derivatives. Bioorganic and Medicinal Chemistry Letters 7 (1997): 187–192.
OTHER PUBLISHED WORK
These articles, books, and other publications provide summaries of research, historical perspectives, and other references. Many of these works are review articles, papers that synthesize the most pertinent original research in a given field. Additional reference materials were used as sources for this book, but the following represent the most key reports.
Arnold, K. After 30 years of laboratory work, a quick approval for STI571. Journal of the National Cancer Institute 93 (2001): 972–973.
Baltzer, F. “Theodor Boveri: The Life of a Great Scientist 1862–1915.” Berkeley: University of California Press, 1967. Available online at http://9e.devbio.com/article.php?ch=2&id=25.
Bazell R. HER-2. New York: Random House, 1998.
Bishop, J. M. Oncogenes. Scientific American 246 (1982): 68–78.
Cohen, P. Protein kinases—the major drug targets of the twenty-first century? Nature Reviews Drug Discovery 1 (2002): 309–315.
Druker, B. J. Translation of the Philadelphia chromosome into therapy for CML. ASH 50th anniversary review. Blood 112 (2008): 4808–4817.
Druker, B. J., C. L. Sawyers, R. Capdeville, J. M. Ford, M. Baccarani, and J. M. Goldman. Chronic myelogenous leukemia. Hematology. American Society of Hematology Education Program (2001): 87–112.
Hunter, T. The proteins of oncogenes. Scientific American 251 (1984): 70–79.
———. Treatment for chronic myelogenous leukemia: The long road to imatinib. Journal of Clinical Investigation 117 (2007): 2036–2043.
Hunter, T., and W. Eckhart. The discovery of tyrosine phosphorylation: It’s all in the buffer! Cell S116 (2004): S35–S39.
Kharas, M. G., and G. Q. Daley. From hen house to bedside: Tracing Hanafusa’s legacy from avian leukemia viruses to SRC to ABL and beyond. Genes & Cancer 1 (2011): 1164–1169.
Kurzrock, R., H. M. Kantarjian, B. J. Druker, and M. Talpaz. Philadelphia chromosome–positive leukemias: From basic mechanisms to molecular therapeutics. Annals of Internal Medicine 138 (2003): 819–830.
Langreth, R. Big bucks. Forbes, May 21, 2007.
Lawce, H. Genetic technology and CML: Culture and history. Journal of the Association of Genetic Technologists 37 (2011): 29–30.
Lydon, N. B. Attacking cancer at its foundation. Na
ture Medicine 15 (2009): xix–xxiii.
Lydon, N.B., and B. J. Druker. Lessons learned from the development of imatinib. Leukemia Research 28, supplement 1 (2004): S29–S38.
Monmaney T. A triumph in the war against cancer. Smithsonian, May 2011.
Mueller, J. M. Taking TRIPS to India—Novartis, Patent Law, and Access to Medicines. New England Journal of Medicine 256 (2007): 541–543.
Mukherjee, S. The Emperor of All Maladies. New York: Scribner, 2010.
Nowell, P. C. Genetic alterations in leukemias and lymphomas: Impressive progress and continuing complexity. Cancer Genetics and Cytogenetics 94 (1997): 13–19.
Pollack, A. Therapies for cancer bring hope and failure. New York Times, June 15, 2010.
Rosenberg, N., and K. Beemon. Mechanisms of Oncogenes by Avian and Murine Retroviruses. In: Current Cancer Research. New York: Springer Science + Business Media, 2012.
Rous, P. Nobel Lecture, 1966. Available online at http://www.nobelprize.org/nobel_prizes/medicine/laureates/1966/rous-lecture.html.
Sharat Chandra, H., N. C. Heisterkamp, A. Hungerford, J. J. D. Morrissette, P. C. Nowell, J. D. Rowley, and J. R. Testa. Philadelphia Chromosome Symposium: Commemoration of the 50th anniversary of the discovery of the Ph chromosome. Cancer Genetics 204 (2011):171–179.
Temin, H. M. Mechanism of cell transformation by RNA tumor viruses. Annual Review of Microbiology 25 (1971): 609–648.
Vasella, D., and R. Slater. Magic Cancer Bullet. New York: HarperCollins, 2003.
US Department of Health and Human Services. Office of Inspector General. The Orphan Drug Act—Implementation and impact. May 2001. OEI-09-00-00380. Available online at http://www.dhhs.gov/progorg/oei.
US Food and Drug Administration. Summary basis of approval (SBA) for Gleevec. Document provided by FOI Services. Document number 5202527.
Wade, N. Powerful anti-cancer drug emerges from basic biology. New York Times, May 8, 2001.
Weiss, R. A., and P. K. Vogt. 100 years of RSV. Journal of Experimental Medicine 208 (2011): 2351–2355.
Wong S., and O. N. Witte. The BCR-ABL story: Bench to bedside and back. Annual Review of Immunology 22 (2004): 247–306.
ACKNOWLEDGMENTS
Thanks to all of the scientists and clinicians who agreed to interviews, including Brian Druker, Naomi Rosenberg, Owen Witte, David Baltimore, Nick Lydon, Alex Matter, Daniel Vasella, Charles Sawyers, Steve Goff, Sir Philip Cohen, Ray Erickson, Herb Abelson, Michael Mauro, Peter Nowell, Janet Rowley, Jürg Zimmermann, Elisabeth Buchdunger, Helen Lawce, Renaud Capdeville, John Goldman, Peter Traxler, Moshe Talpaz, Brian Hemmings, Peter Parker, Emil Freireich, George Daley, J. Michael Bishop, Nora Heisterkamp, Kara Johnson, and Joel Crouch. Additional thanks go to Steve Goff and Helen Lawce for reading and commenting on early drafts. I thank Gary Eichner, Judy Orem, Frank Orem, Alice Hungerford, Hans Loland, Beverly Alex Owens, Kelly Mitchell, Suzan McNamara, Alexandra Hardy, and Jennifer Gangloff for sharing their stories and allowing me a glimpse into their personal lives. Thanks also to LaDonna Lopossa, Dori Mortenson, Jay Weinstein, and Virginia Garner. I also want to recognize all those who contributed to the STI Gazette and the “Appreciation Album,” both of which were source material for this book.
To all of these individuals, I hope I have shown respect in walking the hallowed ground of other people’s lives.
This book emerged through the encouragement and support of many people. At my publisher, The Experiment, those people are Matthew Lore and Nicholas Cizek. Thanks also to Russell Galen, literary agent. I’m grateful to Sarah Bowden and Elisa Williams at OHSU and Sarah Kestenbaum at Ruder Finn for their assistance, and to Norma McLemore for copyediting and Jason Rothauser for proofreading. Steve Kurlander, Paul McDaniel, Tanya McKinnon, Siena Siegel, and Joy Pincus were also all part of this book coming to life.
I thank my family for giving me space, inspiration, and comic relief.
I have done my best to tell this story accurately, referring to the published literature to check the science and the data and, as much as possible, cross-checking each person’s memory of the events described in this book. Any errors, omissions, or oversimplifications are my own and should not be misconstrued as a reflection on anyone mentioned above.
INDEX
A
Abelson, Herb
career, 57, 63, 67, 88
research, 58, 67, 76, 78, 87, 99
Abelson virus
cloning, 77
discovery, 58
gag/abl fusion gene, 83
genome, 78
Goff’s work on, 76
transformation system, 67, 68, 69, 71
Witte’s work on, 70
abl gene, 78, 82, 84
Abl kinase, 73, 74, 87, 113
abl oncogene, 78
abl probe, 82
Abl protein, 72, 73, 80, 88, 118, 126
academia-industry collaborations, 117, 130, 262
accelerated approval, 214, 215, 230
acquired resistance, 250, 251
acute lymphoblastic leukemia, 22
acute myeloid leukemia (AML), 22, 39
acute promyelocytic leukemia, 39
adenosine, 47
adenosine triphosphate. See ATP
American Society of Hematology (ASH)
phase I study results presentation (1999), 208, 210, 213
preclinical results presentation, 150
Amgen, 157
AML. See acute myeloid leukemia
anti-kinase drugs, 107, 128
antibodies, 69, 102
against phosphotyrosine, 102, 116
antifolates, 59
antigens, 61
ara-C, 193, 205
aromatase inhibitors, 107
ATP (adenosine triphosphate), 47, 54, 73
B
B-cell cancer, 61
B-cell leukemia, 76, 81
B cells, 61
b-raf gene, 268
baculovirus, 115
Bagby, Grover, 136, 137, 150
Baltimore, David
about, 67, 73, 77, 152
career, 30, 64, 65
lab, 65, 68, 69, 70, 71, 72, 75, 76, 77, 82, 83, 86, 88, 102, 127
research, 30, 64, 65, 68
banding techniques, 37, 58, 88
Barbacid, Mariano, 98
Basel (Switzerland), 110
Bayh-Dole Act, 263
bcr/abl gene, 85, 127
Bcr/Abl kinase, 89
inhibitor drug testing, 138
Bcr/Abl protein, 86, 89, 102, 118, 127
Bcr/Abl tyrosine kinase, 86, 106, 118
bcr gene, 84, 85
“bench to bedside,” 100
Beth Israel Hospital (Boston), 134
Bishop, J. Michael
about, 50
career, 43
research, 41, 46, 68, 72, 75, 77, 78, 88, 98, 99
Blanke, Charles, 247
Blasdel, Carolyn, 10, 186, 218, 270
“blast crisis,” xiii, 5, 37, 86, 176, 178, 196, 198, 204, 216, 218, 226, 249
Blueprint Medicine, 269
bone marrow transplants, 90, 161
Boveri, Theodor, 34
Boyer, Herb, 50
brain cancer, 106, 247
brand name, 231
breakpoint cluster region, 84
breast cancer, 114, 187, 235, 266
Bristol-Myers Squibb, 257, 258
Buchdunger, Elisabeth
about, 110, 141, 146, 150
career, 116, 157
research, 125, 126, 128, 148, 163
Bullitt, John, 96
C
CAMK family, 266
Canaani, Eli, 84, 118
cancer
about, 13
appearance of new mutations, 267
Druker’s interest in, 52
genetic abnormalities and, 22, 29, 34, 45, 267
kinases and, 89, 92, 106, 118
mutations and, 15, 17, 83, 252, 260, 261, 267
as tolerable chronic condition, 267
t
ranslocations and, 39
transmission, 27
triggering, 30
tyrosine and, 55, 58
and viruses, 27, 30, 58, 88
cancer research, 96, 261
cancer treatment, xi, 59, 93
antifolates, 59
bone marrow transplants, 90, 161
chemotherapy, 90
cisplatin, 109
corticosteroids, 59
cost to patient, 243, 259, 265
crizotinib, 268
dasatinib, 257, 258
delivery systems, 148
drug resistance, 248, 257, 261
erlotinib, 265
inadequacy of, 101
interferon, 105, 181, 189, 191, 205, 219, 243
isoquinolinesulfonamides, 110, 123
lapatinib, 266
Matter on, 104
Medicare coverage for, 243
nilotinib, 258
ponatinib, 260
poverty and, 264
sunitinib, 266
tamoxifen, 132, 235
targeted therapy, 109, 266, 267
See also drug development; Gleevec
Capdeville, Renaud, 213
Castagna, Monique, 106
cell theory, 16
CGP-53716 (Ciba-Geigy), 138
CGP-57148B (Ciba-Geigy)
animal testing, 152
development of, 128, 138
drug candidate testing, 138
human testing, 154
intravenous formulation, 149, 157
investigational new drug (IND) application, 154
limited market for, 142, 145, 169
marketing projections for, 169
marrow-cleaning approach, 145
method of delivery, 149, 155
oral formulation, 149
phase I clinical trial, 146, 154
presentation of preclinical results at conference, 150
publication of preclinical studies, 149
See also STI-571 (Novartis)
chat rooms, phase I patients, 199
chemotherapy, 90, 108
ara-C, 193, 205
cisplatin, 109
goal of, 180
interferon, 105, 181, 189, 191, 205, 219, 243
tamoxifen, 132, 235
See also cancer treatment
The Philadelphia Chromosome Page 31