The Road to Precision: Targeted Cancer Drugs Move from Table to Trials to Bedside

In 1972, Janet Rowley sat at her dining room table and cut out tiny chromosomes from photographs she had taken in her lab. One by one, she cut out the little figures that her children mockingly called paper dolls. Then she carefully arranged them into 23 identical pairs and warned her children not to sneeze.

The physicist and researcher had just mastered a new technique for staining chromosomes during a sabbatical year at Oxford. But it was in the dining room of her Chicago home that she made the discovery that would radically change the course of cancer research.

When she looked at the chromosomes of a patient with acute myeloid leukemia (AML), she found that segments of chromosomes 8 and 21 had broken off and switched places – a genetic swap called a translocation. She looked at the chromosomes of other AML patients and found the same change: the 8;21 translocation.

Later that year, she observed another translocation, this time in patients with a different type of blood cancer, called chronic myeloid leukemia (CML). CML patients were known to carry a puzzling abnormality in chromosome 22 that made it appear shorter than normal. This abnormality was called the Philadelphia chromosome after it was discovered by two Philadelphia researchers in 1959. But it wasn’t until she studied her carefully laid dining table up close that she understood why chromosome 22 was shorter: a piece of it had broken off and swapped places with a small section of chromosome 9, a 9;22 translocation.

Rowley was the first to prove that genetic abnormalities caused cancer. She published her findings in 1973, with the CML translocation published in a single-authored study in Nature. In the years that followed, she strongly advocated that the abnormalities were significant for cancer. But she was initially met with skepticism. At the time, many researchers believed that chromosomal abnormalities were the result of cancer, not the other way around. Rowley’s findings were dismissed by the prestigious New England Journal of Medicine. “At first, I felt a kind of amused tolerance,” she said before her death in 2013.

The birth of targeted treatments

But the evidence quickly mounted. In 1977, Rowley and two colleagues at the University of Chicago identified another chromosomal translocation—15;17—that causes a rare blood cancer called acute promyelocytic leukemia. By 1990, more than 70 translocations had been identified in cancers.

The significance of this mutation soon grew. After Rowley discovered the 9;22 translocation in chronic myeloid leukemia (CML), researchers discovered that the genetic swap creates a fusion of two genes. Part of the ABL gene, normally found on chromosome 9, attaches to the BCR gene on chromosome 22, creating the cancer-causing BCR::ABL fusion gene on chromosome 22. This genetic fusion encodes a signaling protein, a tyrosine kinase, that is permanently stuck in “on” mode. As such, it perpetually triggers signaling pathways that cause white blood cells to multiply out of control.

In the mid-1990s, researchers developed a drug that blocks the BCR-ABL protein, a tyrosine kinase inhibitor (TKI) called imatinib. In patients in the chronic phase of CML (about 90% of CML patients), imatinib increased the 10-year survival rate from less than 50% to just over 80%. Imatinib (sold as Glivec or Glivec) was approved by the Food and Drug Administration in 2001, marking the first approval of a cancer treatment targeting a known genetic alteration.

The success of imatinib has enabled targeted cancer therapies, or precision medicine, to take off. In the early 2000s, researchers focused heavily on precisely identifying the genetic underpinnings of cancer. At the same time, the revolutionary development of next-generation genetic sequencing provided fuel for this burgeoning field. This technology has made it easier to identify the genetic mutations and abnormalities that cause cancers. Sequencing is now considered standard care in the diagnosis, treatment, and management of many cancers.

The development of gene-targeted cancer therapies has exploded. Classes of tyrosine kinase inhibitors (TKIs), such as imatinib, have expanded particularly rapidly. There are now more than 50 FDA-approved TKIs targeting a wide variety of cancers. For example, the TKIs lapatinib, neratinib, tucatinib, and pyrotinib target human epidermal growth factor receptor 2 (HER2), which is involved in some breast and gastric cancers. The TKI ruxolitinib targets Janus kinase 2, which is commonly mutated in myelofibrosis, a rare blood cancer, and polycythemia vera, a slow-growing blood cancer. Patients with CML now have a choice of five TKI therapies.