The Philadelphia Chromosome

by Jessica Wapner

  The evolving survival data from the initial Gleevec trials continues to be closely scrutinized, in part to understand how the drug works and in part to inform public and scientific opinion on targeted therapy in general. In 2012, ten-year survival data on 368 patients treated at MD Anderson Cancer Center were published. All of the patients were from the earliest studies, restricted to those who had stopped responding to interferon. Ten years after entering the clinical trial, 68 percent—250 patients—were still alive. CML was progressing in less than five of those patients. A portion of the surviving patients had stopped responding to Gleevec at some point over the years, and had then been switched to a second-generation inhibitor. Almost all of the patients who’d survived ten years since enrolling in the study had had a complete cytogenetic response—no evidence of the Philadelphia chromosome—emphasizing the strong link between this depth of response and survival. It is important to note that this particular study wasn’t a comparison; no other treatment arm was tracked simultaneously, a design that tends to diminish the robustness of the findings, as does the fact that the study was done at just a single cancer center. But the ten-year survival data can be viewed in light of the pre-Gleevec median survival time of four to six years. Before 2001, no one diagnosed with CML was told he or she might live for ten years or more.

  To Druker, high expectations were part of what will come to be seen as just the very earliest days of a new time for cancer care. As he sees it, the clarity of knowing that cancer is a genetic disease is the starting point for what may require twenty years of research or more before the next Gleevec comes along. As tumors are genetically sequenced, cancer patients will be diagnosed according to their molecular profile. At the same time, ongoing research to profile experimental compounds according to what molecules they likely target can dovetail with tumor profiling. “Let’s sequence every tumor and figure out what drugs match that tumor,” said Druker. Genetic profiling of patients can also inform treatment decisions, because some patients may metabolize drugs faster than others, for example, a quirk that could be spotted in a DNA sequence. Then, patients can be matched to a treatment for their particular tumor and personal genetic profile.

  The approach has been widely chronicled, hailed as the next big thing for cancer, and greeted with equal parts skepticism and optimism. Michael Mauro cites the recently approved drug crizotinib, for lung cancer, as the latest proof of the principle. The drug targets an abnormality present in just a subset of lung cancer patients and will be given only to those patients. A mutation in a gene called b-raf was recently found to be present in all patients with hairy cell leukemia. Although the disease can’t be triggered by forcing a b-raf mutation, it can be stopped by blocking the mutation. Hairy cell leukemia is rare and already has an effective treatment, but Mauro sees the finding as evidence of the validity of continuing to uncover the genetic roots of cancer. “It’s history starting to repeat itself,” he said.

  In addition to his work at OHSU, Druker has also launched Blueprint Medicine, based in Cambridge, Massachusetts, with Nick Lydon. The company’s research is aimed at screening tumors and compounds for potentially relevant genetic abnormalities. Other companies are whittling down the time required for genome sequencing to forty-eight hours. Others are focused on developing technology to identify the four or five driver mutations out of the 200 or more that may be present in a given tumor sequence at any given moment.

  “There would be a Gleevec for every cancer,” Druker said of his hope for the future of cancer treatment, the drug now as much a symbol as it is a medication. The drug continues to guide his vision for cancer research, one that is inextricably linked to his experience over the last twenty years. The lessons of Gleevec—the biologic principle that it proved and the business model it created—continue to inform his work. “It’s all about the target. Identifying the right target, getting a good drug for that target,” said Druker, “and not worrying about what the market size is.”

  Epilogue

  _______

  SURVIVAL TIME

  Gary Eichner, Druker’s patient that chilly February morning in 2012, knew none of this history as he lay on the exam table with a needle stuck into his lower back. He had never heard of Peter Nowell or David Hungerford. He knew nothing about the Abelson virus and how researchers had used it to unravel the cause of CML. He was unaware of the legacy of kinase research, of the painful treatments that he’d never have to experience, of the role that his own doctor had played in securing his future. And as Carolyn Blasdel told Eichner the good news over the phone, that none of his white blood cells contained the Philadelphia chromosome, he had no idea of just how much history was packed into that single sentence—words that were, for him, the difference between life and death.

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  What he did know, and perhaps all he needed to know, was that he would live. That he would be there for his teenage son for the foreseeable future. That a disease that might have killed him would instead probably have little to no impact on his life and the lives of his loved ones. “What is my chance in the next five years of not relapsing? It looks good,” he said. “I wake up every morning feeling extremely fortunate.”

  THE FINAL ISSUE of the STI Gazette was published in the spring of 2002. With Gleevec now approved and widely available, and the tight-knit trial community now dispersed as people resumed their normal lives, the newsletter had run its course. Orem was also ready to move on, though her home was now firmly in Portland. She and her husband had bought a house there, and she’d taken all her belongings out of storage. It was time to lay back down some roots. “I think I’m going to live,” she’d said to her husband. “I don’t think we should be thinking about this as a temporary thing.” She would continue to do well on the drug, remaining active with her family, including the grandchildren who’d been born after she was diagnosed. By 2012, she held the record for the longest amount of time on Gleevec.

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  Others she’d known over the years were moving on, too. Suzan McNamara would continue to do well. She married the man who’d traveled with her to Portland when she’d been at her sickest. After several years of agreeing to requests from Novartis to speak about Gleevec and even appearing in some ads, McNamara retreated from the role of spokesperson. She didn’t want to think of herself as a CML patient anymore; she just wanted to live her life.

  Bud Romine never suffered from CML after the Gleevec trials. He died years later of unrelated causes.

  Closing the newsletter was a bittersweet farewell for Orem. As in nearly every issue, Druker contributed his personal message. “Those of you who were the early participants in these clinical trials are the true pioneers. I will continue to greatly value our partnership in bringing Gleevec to the forefront. Patients have been extraordinarily generous in their thanks. No award, no media appearance, and no titles will replace the feeling of knowing that my work has made a difference in people’s lives,” he wrote.

  Michael Mauro wrote likewise. “The best way to sum up these efforts is to say thank you, to you, the heroes, the brave souls—who were pioneers in historical trials that redefined treatment of an illness.”

  After some final brief memoirs, Orem signed off, her final words capturing exactly how the drug had changed her life and the lives of so many others.

  “Thanks,” she wrote. “Enjoy life.”

  PLATES

  1. Peter Nowell, MD, (left) and David Hungerford, codiscoverers of the Philadelphia chromosome in 1959 (credit).

  2, 3. These microscope photographs are from Nowell and Hungerford’s first full-length publication on the Philadelphia chromosome. Both figures show human chromosomes halted during cell division using the innovative process developed by Nowell. Figure 1 is from a healthy subject. In figure 2, an arrow points toward the abnormally small chromosome 22 in a cell from a patient with CML. Although staining techniques were rudimentary, Hungerford was able to spot this mutation—the Philadelphia chromosome (credit).

>   4. Cell cultures from Naomi Rosenberg’s experiments with the Abelson virus. Left: Cells unexposed to the virus remain invisible to the naked eye. Right: Each black dot is a visible cluster of cells that arose from a single, virus-infected cell (credit).

  5. The Barred Plymouth Rock hen brought to Peyton Rous in 1909. The virus isolated from the hen’s tumor was instrumental in unraveling how viruses trigger cancer transformation, and ultimately led to the discovery that cancer-causing genes come from healthy genes (credit).

  6. A bone marrow biopsy from a patient with CML. This sample is overcrowded with white blood cells and platelets, making it far more condensed than normal bone marrow. One of the first symptoms of CML is bone pain resulting from this excess proliferation of blood cells inside the marrow (credit).

  7. (credit)

  8. Janet D. Rowley, MD, who in 1972 discovered that the mutated form of chromosome 22 was part of a translocation, in which a piece of chromosome 22 and a piece of chromosome 9 swap places (credit).

  9. In the Philadelphia chromosome translocation, the abl gene, usually on chromosome 9, moves next to bcr, on chromosome 22, resulting in a mutant gene, bcr/abl. The fusion of these genes, the defining feature of the Philadelphia chromosome, causes chronic myeloid leukemia (credit).

  10. A karyotype from a patient with chronic myeloid leukemia, created with the banding techniques that became available in the 1970s, showing the extended chromosome 9 and truncated chromosome 22 (the Philadelphia chromosome) (credit).

  11. (credit)

  12. A sample of blood from a patient with CML. The excess abnormal white blood cells that are the hallmark of this disease are stained purple (credit).

  13. A FISH (fluorescence in situ hybridization) image of chromosomes from a patient with CML. The red dots indicate the abl gene, and the green dots indicate the bcr gene. The yellow dots indicate chromosomes on which bcr and abl are fused together (credit).

  14, 15. Jürg Zimmermann and Elisabeth Buchdunger of Novartis Pharmaceuticals. Zimmermann and Buchdunger worked together to create the first tyrosine kinase inhibitor. Zimmermann led the effort to synthesize experimental compounds, and Buchdunger tested each new compound for possible anticancer activity. The lead drug candidate that emerged from their work blocked the Bcr/Abl kinase and was named CGP-57148B, then STI-571, and finally Gleevec (imatinib mesylate) (credit, credit).

  16. 2000 Warren Alpert Foundation Prize recipients. From left to right: Owen Witte, Nicholas Lydon, Brian Druker, Alex Matter, and David Baltimore. The award was given to all five individuals for their research that led to the development of the first tyrosine kinase inhibitor (credit).

  17. Brian Druker and LaDonna Lopossa, the sickest patient to enroll in the STI-571 clinical trial at OHSU. Lopossa had chosen her burial plot shortly before she began treatment in 2000; this photo was taken in 2011 (credit).

  18. A 400-milligram pill of Gleevec, a typical daily dose for someone with CML (credit).

  19. A 2010 gathering at Fox Chase Cancer Center in Philadelphia to celebrate the 50th anniversary of the discovery of the Philadelphia chromosome (people whose names are in bold below appear in the book) (credit).

  Back row: Felix Mitelman, Alfred Knudson, Joseph Testa, Peter Nowell, Nicholas Lydon, William Sellers, Owen Witte. Front row: Janet Rowley, Alice Hungerford (holding a photo of her late husband David), John Goldman, Nora Heisterkamp, Charles Sawyers, Hope Punnett.

  20. This photograph of Gary Eichner and his son, Tuff, was taken in 2013, about a year after Eichner began treatment for chronic myeloid leukemia (credit).

  21. A 2001 advertisement for Gleevec featuring Suzan McNamara, who led the patient-driven effort to request that Novartis speed up production of the drug in 1999 (credit).

  GLOSSARY

  Abelson virus A cancer-causing virus discovered by Herb Abelson. While researching the cellular mechanisms of cancer, he exposed healthy mice to the Moloney virus, which captured the abl gene from their DNA to become the Abelson virus. The virus induces B-cell tumors in mice.

  abl The gene that encodes the Abl protein kinase. When combined with the gene bcr via a translocation, it forms bcr/abl, the mutant gene that induces CML.

  Abl The protein product of the abl gene, which is named for the Abelson virus. The fusion protein Gag/Abl, a tyrosine kinase, drives the cancer-causing action of the virus. Another tyrosine kinase, Bcr/Abl, is part of the mechanism that causes CML.

  Acute leukemia A type of leukemia characterized by rampant production of nonfunctioning blood cells. This type of cancer progresses rapidly, whereas chronic leukemia progresses slowly. Acute leukemias are the most common types of cancer in children.

  Amino acids Organic molecules that serve as the building blocks of all proteins.

  Antibody A protein produced by the immune system to target harmful intruders such as viruses. In biological research, antibodies are often a useful way of detecting a substance; if an antibody is present, its antigen, or target, must be present.

  Antigen The target of an antibody. Each antibody targets a unique antigen.

  ASH The American Society of Hematology. It was at the ASH annual meeting in 1999 that Brian Druker gave a landmark presentation on the effectiveness of STI-571, the drug that would become Gleevec.

  ATP Adenosine-5’-triphosphate, an essential molecule used to store and transfer energy in cell metabolism. The normal function of a kinase is to take one phosphate from an ATP molecule and attach it to another protein in a reaction called phosphorylation. Uncontrolled phosphorylation of the protein responsible for white blood cell production causes CML.

  B cells A type of lymphocyte, one of the varieties of white blood cells. B cells are activated by helper T cells and produce antibodies to fight invaders. B cells are also the target of the Abelson virus, a key tool in early cancer research.

  bcr A proto-oncogene located on chromosome 22 at the point where the chromosome breaks and swaps genetic material with chromosome 9 (the “breakpoint cluster region”) to become the Philadelphia chromosome. This translocation brings bcr into proximity with abl, to form the bcr/abl fusion gene that is the cause of CML.

  Bcr The protein product of the bcr gene, and a component of the fusion protein Bcr/Abl.

  Bcr/Abl The protein product of the bcr/abl gene, this mutant tyrosine kinase is the mechanism for CML. Bcr/Abl phosphorylates a protein that triggers the creation of white blood cells, driving this usually tightly regulated process out of control and resulting in excessive production of blast cells.

  Blast cells Immature white blood cells. CML is characterized by unregulated production of these nonfunctional cells, and the disease’s progress can be measured by the concentration of blast cells in a patient’s blood.

  Blast crisis stage The final stage of CML, when the patient’s blood consists of at least 30 percent blast cells. At this stage, without treatment, the disease progresses rapidly and survival time is limited.

  Chromosome An organized structure of DNA found in the nucleus of a cell. The human genome consists of 46 chromosomes, with 23 coming from each parent.

  Chronic leukemia A type of cancer in which abnormal, poorly functioning blood cells are produced in excess. Onset is typically slow, and the disease generally affects adults.

  Clinical trial A series of studies in which a new drug is tested for effectiveness and safety. Several rigorous stages of testing are required before a drug can be approved by the FDA for marketing.

  CLL Chronic lymphocytic leukemia, a cancer similar to CML that begins in the bone marrow but then moves to the lymph cells.

  CML Chronic myeloid leukemia, the cancer caused by the Philadelphia chromosome mutation and targeted by the drug Gleevec. Before Gleevec, the most effective CML treatment could prolong life for only a few years, but the disease is now a manageable condition when treated with Gleevec or other tyrosine kinase inhibitors.

  Cytogenetics The study of the connection between genes and diseases. Among patients with CML, a cytogenetic response to
treatment means that the number of cells in the bone marrow containing the Philadelphia chromosome mutation, the root cause of the disease, are reduced.

  Dasatinib A drug originally created to inhibit T cells in the immune system, it was found to be effective against CML and is part of the second generation of tyrosine kinase inhibitors for CML.

  DNA The double-helix organizational structure of the genetic code. DNA is made of genes that encode the proteins responsible for nearly every biological function.

  EGFR Epidermal growth factor receptor, a kinase that is a member of the erbB family of proteins. It has been considered a promising target for kinase inhibition because it is found in a variety of common cancers. Another member of the erbB family, Her2, is found in some breast cancers.