Gleevec’s False Dawn

The cancer drug known as Gleevec (United Stated) or Glivec (Europe) is the unquestioned superstar of the genetic approach to cancer. It is the LeBron James, Michael Jordan and Wilt Chamberlain all rolled up into one. It is used in the treatment of chromic myelogenous leukemia (CML), a relatively rare cancer. Before Gleevec, CML killed 2300 Americans and after Gleevec, in 2009, it only killed 470 people — all using an oral medication with virtually no side effects. This is a truly amazing drug, so dramatically successful that it was thought to be the herald of an entirely new era of chemotherapy. At its introduction in the early 2000s, it was the dawn of a new age of targeted genetic ‘cures’ for cancer. Gleevec was supposed to be the beginning, not the end. But like any one-hit wonder, the first turned out to be the best.

Genetic treatments will work wonders for genetic diseases, but the specific circumstances surrounding CML did not apply to most of the common cancers (breast, colorectal, prostate) that we face today. CML is almost completely a genetic disease caused by the mixup of chromosomes during cell growth. Normally, when cells divide, they provide exactly the same chromosomes to each new cell. However, in CML a piece of chromosome 9 ended upon chromosome 12 and vice versa. Named for the city of its discovery, it was termed the ‘Philadelphia chromosome’. Virtually all patients with CML had this Philadelphia chromosome, and in 1960, it became clear that this genetic aberration caused the cancer.

This swap in chromosomes caused the cells to make an abnormal protein (BCR/ABL). This protein is a signalling molecule called a kinase, which works like an accelerator on cell growth. Normally, this kinase would be turned on and off according to a precise pattern, just as you would use the accelerator on your car carefully speed up or slow down, according to traffic signals. The abnormal bcr/abl protein turned cell growth ‘on’ and never let up. It stepped on the gas full bore, and never let up.

The solution, then is to block this bcr/abl kinase to ease the gas on cell growth and cause the cancer to subside. In 1993, the drug firm Ciba-Geigy (now Novartis) tested several kinase inhibitor, and selected the most promising candidate. This drug, now called Gleevec, could block the kinase in question so human drug trials began. The Phase I…