Indeed, some experts note that “targeted therapies” can be a buzz term. Every drug is targeted in some sense. Furthermore, a number of targeted therapies, despite their name, inadvertently hit other molecules, much like traditional chemotherapeutic drugs.
How Gleevec shook up cancer therapy
Targeted therapeutics took the cancer world by storm more than a decade ago. In 1998, trastuzumab, better known by its trade name Herceptin, came out of Genentech. It was an antibody that bound to HER2/neu receptor on breast cancer cells. But in 2001 a molecule came along that made scientists and oncologists take note. It targeted a kinase.
“Ever since the discovery of kinases and signaling phosphorylation in the 1960s, the consensus was you’d never be able to make a specific kinase inhibitor because they all bind ATP in exactly the same way,” says David Stokoe of Genentech. Kinases are involved in signaling pathways that control critical functions, such as the cell cycle, protein expression and genome stability. As the first kinase structures appeared in the early 1990s and the Human Genome Project eventually showed that there were at least 500 of them, many scientists doubted if it would be possible to get an inhibitor specific enough to hit just one or two.
Imatinib, best known by its U.S. tradename Gleevec and marketed by Novartis, washed those doubts away. Developed in the late 1990s by Nicholas Lydon, formerly at Novartis and now at Blueprint Medicines, Brian Druker of Oregon Health and Science University, Janet Rowley at the University of Chicago and others, imatinib was the first drug to inhibit specifically the Bcr-Abl receptor tyrosine kinase that is the root cause of chronic myelogenous leukemia. The constitutively active Bcr-Abl kinase is produced by a reciprocal translocation between chromosomes 9 and 22. Ninety-five percent of CML patients have this mutation, which also shows up in several other cancers.
Unlike conventional chemotherapeutic drugs, imatinib targeted only the cancerous cells expressing the mutant kinase and left alone the cells lacking it. The FDA approved the drug in May 2001, and Time magazine put the drug on the cover as the magic bullet to cure cancer.
Although designed as an inhibitor of Bcr-Abl, the compound also inhibits the platelet-derived growth factor receptor, a cell-surface tyrosine kinase, and c-kit, a cytokine receptor on hematopoetic stem cells that is a tyrosine kinase. Mutant PDGF receptors are involved in chronic myelomonocytic leukemia and c-kit mutations are found in stomach cancers. For these reasons, the FDA expanded its approval for imatinib to treat 10 different cancers by 2011. In January, Lydon, Druker and Rowley were awarded the Japan Prize for their work.
Imatinib drove home the point that, although all kinases use ATP, “every enzyme is mechanistically different in atomic detail,” says Schramm. The drug changed the treatment of CML. Prior to imatinib, CML chemotherapies eventually forced patients to get bone-marrow transplants. Now more than 90 percent of CML patients are treated with a pill. Very few go on to have transplants, and the number of deaths caused directly by CML per year is less than 100 in the U.S., says John Byrd of Ohio State University. “The therapy has completely changed how the disease is managed.”
Designing targeted therapies
Imatinib set off the hunt for more targets in cancer. Targets can be defined in several ways. They can be genetic mutations, such as the one that produces Bcr-Abl. Another way to define a target is to pinpoint molecules that are essential in metabolic and signaling pathways. Once a target is identified, scientists also have to make sure that it’s accessible to drugs.