Howard Hughes Medical Institute 2010 Annual Report

Brian J. Druker Charles L. Sawyers

HHMI investigators Brian J. Druker (left) and Charles L. Sawyers

Lasker Honors Long Road to Leukemia Treatment

Decades of deeply collaborative work that no single lab could have accomplished alone led to development of the first treatment that selectively targets a cancer-causing enzyme. In 2009, three scientists were awarded the Lasker–DeBakey Clinical Medical Research Award for the work.

Presented in October to HHMI investigator Charles L. Sawyers of Memorial Sloan-Kettering Cancer Center, HHMI investigator Brian J. Druker of Oregon Health & Science University, and Nicholas B. Lydon, formerly of Novartis, the award recognizes their development of novel drugs for chronic myeloid leukemia (CML), which revolutionized treatment of the once-incurable disease.

The story has its roots in the 1960s, when a team of scientists noticed an abnormally small chromosome in patients with CML. By 1973, they had shown that this chromosome—dubbed the “Philadelphia chromosome” for the city where it was discovered—was a mix-up of genes from chromosomes 9 and 22.

With the advent of genetic mapping a decade later, researchers learned that the chromosome swap causes parts of two separate genes—BCR, from chromosome 22, and ABL, from chromosome 9—to combine into one fusion gene: BCR-ABL. The unique properties of the fusion gene stimulate continuous cell growth, a perfect recipe for creating the uncontrolled growth of cancer—in the case of CML, an overgrowth of white blood cells in the bone marrow.

In the mid-1980s, Druker and Lydon were both studying a class of proteins involved in cell signaling called tyrosine kinases. Because ABL is a tyrosine kinase, Lydon thought that developing a compound to shut off the tyrosine kinase activity of BCR-ABL could be the key to treating CML. Druker had discovered a way to measure tyrosine kinase activity in a cell, which could be used to show when BCR-ABL was shut off.

They began collaborating, with Druker testing compounds that Lydon’s team developed. They narrowed their compounds down to one—imatinib mesylate, or Gleevec—and worked to optimize the drug for humans.

“To accelerate progress, investigators must find ways to encourage academic and industrial collaboration,” wrote Druker in an October 2010 commentary in Nature Medicine. In the case of imatinib, all did what they do well.

“Academics had identified and validated a target, and I had established all the model systems to evaluate compounds,” Druker continued. “Nick [Lydon]’s group had developed compounds and was willing to share their compounds for testing. Then, academics carried out the clinical trials in collaboration with industry.”

In 1995, Druker enlisted Sawyers, a physician-scientist who specialized in CML, to help design clinical trials for Gleevec. Phase I trials began in 1998. Almost immediately, the researchers saw breathtaking results: patients experienced complete remission of CML within weeks of beginning the drug regimen. The Food and Drug Administration (FDA) approved Gleevec for use in CML and a rare form of stomach cancer in 2001.

Over time, however, many patients developed resistance to Gleevec. Sawyers focused on understanding, and treating, these tough cases. He discovered, with the help of HHMI investigator John Kuriyan’s molecular structure of BCR-ABL, that Gleevec-resistant forms of CML had a form of BCR-ABL that had mutated.

Sawyers then collaborated with scientists at Bristol Myers Squibb to find a compound that would block the action of the mutated fusion gene: dasatinib. FDA approved it for use in 2006.

Today, CML is no longer the death sentence it was 10 years ago, and patients with many forms of cancer benefit from treatments based on similar kinase inhibitors. Studies have shown at least 80 percent of Gleevec users were still alive eight to 10 years after beginning therapy, much higher than the historical survival rate of less than 20 percent for CML patients before Gleevec.

“The reason to apply genomics to translational medicine is fairly obvious,” says Sawyers. “But the breadth of expertise ranging from running genomics assays, to the computational biology needed to interpret large data sets, to the pathology expertise to get the appropriate samples prepared so the results are interpretable—all these various moving parts have to come together. If you want to play in that space, you have to collaborate.”

In translational medicine, the challenge, says Sawyers, is teaching young scientists that collaboration pays off more than competitiveness. The shared 2009 Lasker–DeBakey Award, one of the highest honors in all of clinical medicine, recognizes the essential teamwork that led to this success.

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Research Highlights

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Explore the work of HHMI scientists through an interactive feature that highlights some of their notable discoveries in 2010.

Photo Credit: Druker: Valls_OHSUcancer2007_465 – credit: John Valls Sawyers: CHARLES_SAWYERS_003 - credit: Liz Baylen/PR Newswire, ©HHMI