Enzyme A type of protein that facilitates various cellular processes. Protein kinases, which in a mutated form can cause cancer, are a type of enzyme.
FDA The Food and Drug Adminstration, the US organization responsible for approving new drugs for marketing by pharmaceutical companies.
FISH Fluorescence in situ hybridization, a method of analyzing DNA under a fluorescence microscope that highlights particular genes in different colors. This technique allowed scientists to investigate the particular mutation responsible for the Philadelphia chromosome and CML.
Focus assay The technique of exposing healthy cells to a cancer-causing agent in a Petri dish and allowing the resulting cancerous cells to multiply. A method for investigating and quantifying external factors that can induce cancer.
gag A gene present in the Moloney virus, the progenitor of the Abelson virus. This proto-oncogene has the potential to join with abl and produce the harmful tyrosine kinase Gag/Abl.
Gag The protein product of the gag gene. A component of the fusion protein Gag/Abl.
Gag/Abl The protein product of the gag/abl oncogene. Gag/Abl, a tyrosine kinase, is responsible for the cancer-causing activity of the Abelson virus.
Gene A sequence of nucleotides on a strand of DNA or RNA. Genes are the basis of heredity and encode the proteins that drive most cellular functions.
GIST Gastrointestinal stromal tumors. A previously untreatable form of cancer, this disease has been found to respond to treatment with Gleevec.
Gleevec/STI-571 A targeted therapy for CML and the first kinase inhibitor to effectively fight cancer. Gleevec works by inhibiting the unregulated activity of the Bcr/Abl tyrosine kinase. Gleevec has also been found effective against other conditions such as GIST.
Hematologic Relating to the study of the blood. Treatment for CML can be evaluated by measuring a patient’s hematological response, ideally a reduction in their count of cancerous white blood cells.
IND Investigational new drug. A type of application seeking FDA approval for an experimental compound.
Interferon This drug was the only treatment for CML before Gleevec, but its effectiveness was limited and the side effects for patients were severe.
IRIS International Randomized Study of Interferon and STI-571. The phase III trial of the drug that would later be named Gleevec. This final trial for the drug proved it to be an effective treatment for CML.
Karyotype The number and type of chromosomes possessed by an organism. Deviations from a normal karyotype can indicate harmful genetic mutations.
Kinase A type of enzyme that is instrumental to starting processes in the cell. The term is derived from the Greek word kinetic, meaning “motion.” Kinases set off a cascade of signals by plucking a single phosphate from a molecule of ATP and placing it on a protein, activating that protein to do its job. Mutated and malfunctioning kinases are the cause of many cancers.
Kinase inhibitor A compound that blocks the action of a kinase. Gleevec is a kinase inhibitor that binds to the kinase Bcr/Abl at the site where Bcr/Abl normally grabs onto ATP. This arrests the progress of CML because, without ATP, Brc/Abl can no longer phosphorylate the protein responsible for blast cell production.
Kit A tyrosine kinase is inhibited by Gleevec. Kit plays a role in some GIST cancers, and this involvement led to the use of this drug to treat GIST.
Leukemia Cancer of the blood or bone marrow. Many early cancer researchers focused on these and other “liquid cancers,” as the cancer’s presence in the bloodstream made quantifying its progress much more straightforward than with solid tumors.
Moloney virus An RNA virus that causes cancer in mice. Herb Abelson’s research on the virus led to the discovery of the Abelson virus, a key tool in the exploration of cancer.
Mutation An alteration to the nucleotide sequence of an organism’s DNA. While many mutations have no effect at all, some bring about profound changes. The Philadelphia chromosome is the result of a type of mutation known as a translocation.
NIH The National Institutes of Health, a US government agency under the umbrella of the Department of Health and Human Services. The primary outlet by which the US government funds scientific research relating to medicine.
Nucleotides The building blocks of DNA and RNA. The four molecules adenine, guanine, cytosine, and thymine are the individual units that make up genes in DNA. In RNA, uracil takes the place of thymine.
ODA The Orphan Drug Act, a US law passed in 1983 meant to encourage the development of drugs for relatively rare diseases. The law includes financial incentives for drug developers, such as federal funding for clinical trials, tax benefits, and a guaranteed period in which they are the exclusive seller of the drug.
OHSU Oregon Health and Science University. Brian Druker began investigating a new treatment for CML at this university in 1993, and in subsequent years it became known as a premier facility for the treatment of leukemia and other cancers, largely due to Druker’s work.
Oncogenes Genes that cause cancer. Research has revealed that many oncogenes are mutations of genes normally found in healthy organisms that, in their mutated form, can trigger cancer.
PDGFR Platelet-derived growth factor receptor, a kinase found in excess in many types of cancer. Like PKC and EGFR, PDGFR was researched as a target for kinase inhibition because of its presence in several common cancers.
Phase I trial The first stage of human drug testing, a trial that enrolls a small number of patients and begins with very small doses of the drug, gradually increasing the dose over time and monitoring the results. The main goal is to ensure that the drug is safe.
Phase II trial The second phase of human drug testing, a larger trial that involves hundreds of patients at multiple locations. This phase of testing begins to investigate the drug’s effectiveness.
Phase III trial A large drug trial in which patients are randomly assigned either the experimental treatment being tested or the best existing treatment. The effectiveness of STI-571, or Gleevec, was tested against that of interferon.
Philadelphia chromosome (Ph, Ph1) The name coined to describe the abnormally short chromsome 22 found in patients with CML. The mutation behind the shortened chromosome was originally considered by many researchers to be a deletion, but was later found to be a translocation in which genetic material is swapped between chromosomes 9 and 22.
Phosphate A molecule built of one phosphorus atom and four oxygen atoms. ATP, the “fuel” of living cells, includes three phosphate groups. A kinase enzyme initiates a chain reaction (called a signaling cascade or signaling pathway) by removing one phosphate group from ATP and placing it on another protein.
Phosphorylation The process by which a kinase places a phosphate onto another protein, beginning a chain reaction in a cell.
PKC Protein kinase C, a kinase associated with some common cancers. Like PDGFR and EGFR, PKC was originally thought to be a promising target for kinase inhibition.
Polymerase chain reaction A diagnostic test used to gauge a CML patient’s molecular response to treatment. The test measures how many of the patient’s blood cells are carrying the Philadelphia chromosome on a logarithmic scale.
Polyomavirus A cancer-causing virus used in early studies of the mechanics of cancer. Research into polyomavirus revealed that some kinases, particularly tyrosine kinases, are involved in cancer.
Proof of principle A demonstration that a new drug actually works as expected. While many experimental drugs work by a similar mechanism to a drug already on the market and therefore rest on a proven principle, experimental drugs that work by a new, hypothetical mechanism can only gain proof of principle through testing.
Protein A relatively large organic molecule made of amino acids. Proteins are instrumental to many vital processes that take place in a living cell. The amino acid sequence of a protein is encoded by an organism’s DNA, so proteins can be thought of as the means by which an organism’s genes guide the physical processes in its cells.
Proto-
oncogene A normal gene that has the potential to become a cancer-causing oncogene. For example, bcr and abl are normal genes that, when combined via the Philadelphia chromosome mutation, form the oncogene bcr/abl which leads to unrestrained production of white blood cells.
Recombinant DNA A process in which strands of DNA are cut and “pasted” together using specialized, targeted enzymes. Among other capabilities, this technology allows scientists to separate specific genes from the larger genome and study them individually.
Red blood cells Specialized cells that deliver oxygen to other cells in the body.
Retrovirus A virus made of RNA, rather than DNA. These viruses contain the enzyme reverse transcriptase, which allows the virus to make DNA out of RNA as part of its replication process, instead of the other way around. DNA from a retrovirus may then become integrated into the host cell’s own genome.
Reverse transcriptase The enzyme that “reads” the nucleotide sequence of RNA and builds the corresponding sequence of DNA.
RNA The key intermediary between DNA and its protein products. DNA in the nucleus is translated into RNA, which then leaves the nucleus and is translated into the appropriate proteins in the cell. Retroviruses contain RNA rather than DNA.
Rous sarcoma virus (RSV) This virus, discovered in the early 20th century, provided the first evidence that cancer could be triggered in cells by an infection. Later, the new technique called a focus assay revealed this virus to be a retrovirus.
Src The protein product of the src gene. Src is a tyrosine kinase found in normal cells, but has the potential to cause cancer when expressed by a mutated oncogene.
src The gene responsible for the cancer-causing effect of the Rous sarcoma virus. Like bcr and abl, src is a proto-oncogene that is normally found in healthy cells but becomes cancerous when mutated.
Staurosporine One of the first compounds discovered to be a kinase inhibitor (specifically targeting the kinase PKC). Staurosporine is an antifungal agent produced naturally by bacteria.
T cell A type of lymphocyte, one of the varieties of white blood cell. Most T cells are either “killers” that target foreign substances, or “helpers” that trigger other killer cells to act.
Targeted therapy A treatment that works by targeting a specific molecule or chemical in the body. Gleevec is a form of targeted therapy, aimed at the kinase Bcr/Abl. Another example is tamoxifen, which blocks estrogen and is used to treat some types of breast cancer.
Translocation A genetic mutation in which two chromosomes exchange genetic material. The Philadelphia chromosome involves a translocation between chromosomes 9 and 22.
Virus A microscopic biological agent that can only reproduce by infecting living cells. Most viruses consist of just an external protein shell containing a short sequence of DNA (or RNA). A virus infects a host cell and uses the host’s own replication machinery to reproduce.
White blood cells Immune system cells that defend the body from diseases. CML, like other leukemias, causes excessive production of defective white blood cells.
REFERENCES
INTERVIEWS
Interviews with academic scientists, doctors, industry researchers, patients, and industry executives served as a primary source for this book. The following individuals, listed in alphabetical order, were interviewed by the author. Some interviews were conducted in 2007; most were conducted in 2012.
Herbert T. Abelson, David Baltimore, J. Michael Bishop, Carolyn Blasdel, Clara Bloomfield, Sarah Bowden, Elisabeth Buchdunger, Renaud Capdeville, Sir Philip Cohen, Joel Crouch (by e-mail), George Daley (by e-mail), Brian Druker, Gary Eichner, Ray Erikson, Emil Freireich, Jennifer Gangloff, Steven Goff, John Goodman, Alexandra Hardy, Brian Hemmings, Alice Hungerford, Tony Hunter, Kara Johnson, Helen Lawce, Hans Loland, Nick Lydon, Alex Matter, Suzan McNamara, Kelly Mitchell, Peter Nowell, Frank Orem, Judy Orem, Beverly Alex Owen, Peter Parker, Naomi Rosenberg, Janet Rowley, Charles Sawyers, Moshe Talpaz, Peter Traxler, Daniel Vasella, Jackie Whang-Peng, Owen Witte, and Jürg Zimmermann.
ORIGINAL RESEARCH
Insights, history, data, and other information were culled from the scientific literature, conference presentations, newspaper and magazine articles, and a host of other works available in print or online. The following peer-reviewed papers, typically referred to as “original research” among the scientific community, are the published results of the most seminal laboratory experiments and clinical trials chronicled in this book, from the first observation of the Philadelphia chromosome, reported in 1960, to the most recent survival figures among CML patients who have been taking Gleevec since 1998.
Ben-Neriah, Y., G. Q. Daley, A. M. Mes-Masson, O. N. Witte, and D. Baltimore. The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science 233 (1986): 212–214.
Buchdunger, E., A. Matter, and B. J. Druker. Bcr-Abl inhibition as a modality of CML therapeutics. Biochimica et Biophysica Acta 1551 (2001): M11–18.
Buchdunger, E., J. Zimmermann, and H. Mett et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Research 56 (1996): 100–104.
———. Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2- phenylaminopyrimidine class. Proceedings of the National Academy of Sciences of the United States of America 92 (1995): 2258–2262.
Carroll, M., S. Ohno-Jones, and S. Tamura et al. CGP 57148B, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL and TEL-PDGFR fusion proteins. Blood 90 (1997): 4947–4952.
Daley, G. Q., R. A. Van Etten, and D. Baltimore. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247 (1990): 824–830.
De Klein, A., A. G. van Kessel, and G. Grosveld et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia. Nature 243 (1973): 290–293.
Deininger, M. W., J. M. Goldman, N. Lydon, and J. V. Melo. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 90 (1997): 3691–3698.
Demetri, G. D., M. von Mehren, and C. D. Blanke et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. New England Journal of Medicine 347 (2002): 472–480.
Druker, B. J., F. Guilhot, and S. G. O’Brien et al.; IRIS investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. New England Journal of Medicine 355 (2006): 2408–2417.
Druker, B. J., C. L. Sawyers, H. Kantarjian, D. J. Resta, S. F. Reese, J. M. Ford, R. Capdeville, and M. Talpaz. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. New England Journal of Medicine 344 (2001): 1038–1042.
Druker B. J., C. L. Sawyers, M. Talpaz, D. J. Resta, B. Peng, and J. M. Ford. Phase I trial of a specific ABL tyrosine kinase inhibitor, “CGP-57148B,” in interferon-refractory chronic myelogenous leukemia patients. Poster presented at the Annual Meeting of the American Society of Hematology, 1998.
Druker, B. J., M. Talpaz, D. J. Resta, B. Peng, E. Buchdunger, J. M. Ford, N. B. Lydon, H. Kantarjian, R. Capdeville, S. Ohno-Jones, and C. L. Sawyers. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. New England Journal of Medicine 344 (2001): 1031–1037.
Druker, B. J., M. Talpaz, R. J. Resta, B. Peng, E. Buchdunger, J. M. Ford, and C. L. Sawyers. Clinical efficacy and safety of an Abl-specific tyrosine kinase inhibitor as targeted therapy for chronic myelogenous leukemia. Plenary Presentation for the Annual Meeting of the American Society of Hematology, 1999.
Druker, B. J., S. Tamur, and E. Buchdunger et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Medicine 2 (1996): 561–566.
Druker, B. J., S. Tamura, E. Buchdunge
r, S. Ohno, G. C. Bagby, and N. B. Lydon. Preclinical evaluation of a selective inhibitor of the ABL tyrosine kinase as a therapeutic agent for chronic myelogenous leukemia. Blood 86, supplement 1 (1995): 601a.
Eckhart, W., M. A. Hutchinson, and T. Hunter. An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates. Cell 18 (1979): 925–933.
Foulkes, J. H., M. Chow, C. Gorka, A. J. Frackelton, and D. Baltimore. Purification and characterization of a protein-tyrosine kinase encoded by the Abelson murine leukemia virus. The Journal of Biological Chemistry 260 (1985): 8070–8077.
Gale, R. P., and E. Canaani. An 8-kilobase abl RNA transcript in chronic myelogenous leukemia. Proceedings of the National Academy of Sciences of the United States of America 81 (1984): 5648–5652.
Goff, S. P., E. Gilboa, E. N. Witte, and D. Baltimore. Structure of the Abelson murine leukemia virus genome and the homologous cellular gene: Studies with cloned viral DNA. Cell 22 (1980): 777–785.
Gorre, M. E., M. Mohammed, K. Ellwood, N. Hsu, R. Paquette, P. N. Rao, and C. L. Sawyers. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293 (2001): 876–880.
Groffen, J., J. R. Stephenson, and N. Heisterkamp et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36 (1984): 93–99.
Heisterkamp, N., K. Stam, J. Groffen, A. De Klein, and G. Grosveld. Structural organization of the bcr gene and its role in the Ph’ translocation. Nature 315 (1985): 758–761.
Heisterkamp, N., J. R. Stephenson, and J. Groffen et al. Localization of the c-abl oncogene adjacent to a translocation break point in chronic myelocytic leukemia. Nature 306 (1983): 239–242.
Hidaka, H., M. Inagaki, S. Kawamoto, and Y. Sasaki. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry 23 (1984): 5036–5041.
The Philadelphia Chromosome Page 30