Hitting the bull’s-eye pg. 2
Targeted cancer therapies are envisioned as the “magic bullets” of cancer treatment. Ideally, they affect proteins and signaling pathways unique to malignant cells and leave normal cells alone.
While that ideal has not yet been achieved, the contrast to traditional chemotherapy is obvious.
“Chemotherapy drugs control the growth of cancer cells, but they do so in a way that’s kind of like using a hammer to kill a housefly on a table. If you bang the table hard enough, you destroy the fly and the table too,” says David Johnson, M.D., deputy director of Vanderbilt-Ingram and past president of the American Society of Clinical Oncology.
Among the first of the new targeted therapies was Gleevec, whose behind-the-scenes development was described in the book Magic Cancer Bullet by Daniel Vasella, M.D., chairman and chief executive officer of the pharmaceutical company Novartis.
Gleevec bounded onto the world stage in 2001, with accelerated approval from the Food and Drug Administration for the treatment of chronic myelogenous leukemia (CML).
The abnormality that causes CML—the so-called Philadelphia chromosome (named for the city in which it was discovered)—was first described in 1960. It results from a translocation, a rearrangement that fuses two genes from different chromosomes together. This in turn produces an abnormal protein, a tyrosine kinase receptor called bcr-abl, which drives cells to become leukemic. Drugs like Gleevec can inhibit the activity of the aberrant receptor, and thus block cancerous growth.
“Imatinib surprised everyone,” says Mace Rothenberg, M.D., Ingram Professor of Cancer Research at Vanderbilt-Ingram. “Even the sponsor was surprised at how effective that drug was in causing complete hematologic and cytologic remissions, remissions where the Philadelphia chromosome disappeared.
“And this was done by a single pill whose main side effects were skin rash, some weight gain and some edema. This was remarkable.”
In the last five years, investigators have discovered how some patients develop resistance to imatinib, by acquiring additional mutations in the bcr-abl receptor that hinder Gleevec binding. A newly approved drug called dasatinib (Sprycel) is able to bind to the mutated bcr-abl, overcoming resistance to Gleevec in patients with such mutations.