.png)
Curious Dr. George: The U.S. Food and Drug Administration (FDA) approval of imatinib (brand name Gleevec) to treat chronic myelogenous leukemia (CML) in 2001—and later to treat gastrointestinal stromal tumors and other cancers—changed the world for patients from likely early death to an expectation of a long life. In addition, imatinib’s approval is credited with launching the new world of targeted therapy for malignant tumors based upon their molecular characteristics.
No such drug comes to market without the basic science probing and discoveries that underpin drug development. You are the lead author of a 1985 manuscript in the academic journal Nature reporting on the fused transcript of two genes, ABL and BCR, in CML that created a novel hybrid gene product, which was subsequently targeted by drug developers to halt the disease. How did that discovery come about and ultimately lead to clinical trials that launched targeted cancer therapies?
Emma Shtivelman, PhD: More than 40 years ago, I was fortunate to become a PhD student in the laboratory of Dr. Eli Canaani at the Weizmann Institute of Science in Israel. My master’s degree thesis at Moscow State University in Russia had been devoted to the Moloney sarcoma virus, which is used to study cancer in mice. Dr. Canaani’s laboratory worked on oncogenes—genetic mutations that drive cancer, and I was interested in oncogenes, having studied the proto-oncogene MOS in the Moloney sarcoma virus. Joining Dr. Canaani’s laboratory unexpectedly placed me at the center of one of the most important advances in cancer research.
Dr. Canaani was interested in CML, a disease that was almost always fatal within a few years. More than 95% of CML patients carried the same chromosomal abnormality—the Philadelphia chromosome, discovered in 1960 by Dr. Peter Nowell in Philadelphia, giving the abnormality its name. More than a decade later, in 1973, Dr. Janet Rowley made a seminal discovery that the Philadelphia chromosome was a product of a reciprocal translocation between chromosomes 9and 22—a finding that showed, for the first time, that a specific chromosomal alteration could cause a specific human cancer.
In 1984, Dr. Canaani published an important paper identifying an altered transcript of the known oncogene ABL (on chromosome 22) in the leukemic cells of CML patients. My PhD thesis was devoted to the identification of the oncogenic product of the ABL RNA that was affected by the Philadelphia chromosome. Today, this effort would take mere days, but in the mid-1980s, it required months of painstaking work. We constructed cDNA libraries in one phage, isolated bacteriophage clones, performed Maxam-Gilbert DNA sequencing, and manually read radioactive sequencing gels from X-ray films.
We discovered that the beginning of the ABL gene had been replaced by sequences from another gene, BCR, creating the BCR-ABL fusion gene that drives the disease. Our findings, published in 1985, helped establish the molecular basis of CML.
This was the first demonstration that a chromosomal translocation can result in the creation of a fused RNA (and protein) that is likely oncogenic. It was exciting, but none of us imagined how quickly it would transform patient care.
ABL is a type of enzyme known as a tyrosine kinase, and a search for compounds that could block the activity of these enzymes was ongoing, including at the Swiss pharmaceutical company Ciba-Geigy. One of the compounds being studied, CGP57148B (later named STI571) became of high interest to Dr. Brian Druker, a physician-scientist at Oregon Health & Science University. He managed to persuade Ciba-Geigy to provide the drug for laboratory testing and demonstrated that its electively inhibited the growth of CML cells. Even then, convincing the company to move STI571 into clinical trials required years of persistence.
When the first clinical trial began in 1998, the results were extraordinary. Nearly every CML patient achieved remission, and a disease with a median survival of only three to five years became, for most patients, a chronic, manageable condition with life expectancy approaching normal.
The drug, eventually named imatinib (Gleevec) became the first great success of precision oncology, proving that understanding the molecular cause of a cancer could lead to highly effective, targeted therapy.
Looking back, I feel incredibly fortunate to have played a small part in this story. As a graduate student, I spent countless hours pouring sequencing gels and reading DNA sequences from X-ray films, never imagining that this painstaking work would contribute to a treatment that has saved many lives. It remains one of the most rewarding experiences of my scientific career.
Dr. Shtivelman can be reached at emma@cancercommons.org.
.jpg)
.jpg)
