A very important category of cancer-causing mutations do their mischief at the very beginning of the cell division process. These cancer-causing genes, called oncogenes, trick the cell into deciding that it is time to divide, when in fact it is not.
It has been clear for several years that one way to attack cancer would be to somehow mute the overly-loud divide signal being sent to the cell nucleus by oncogenes. Now we are learning how.
Signal Reception Inhibitors. The first step in cell division is the reception by a cell of a divide signal, usually a small molecule called a growth factor. These growth factors bind to special receptor proteins embedded within the cells outer membrane. Like banging on a door, their arrival signals that its time to divide.
In order to get the signal all the way into the nucleus — a very far distance in molecular terms — the cell employs a sort of pony express. The ponies in this case are enzymes called tyrosine kinases. These enzymes add phosphate groups to proteins, but only at a particular amino acid called tyrosine. No other enzymes in the cell do this, so the tyrosine kinases form an elite core of signal carriers not confused by the myriad other molecular activities going on around them.
There are 58 known tyrosine kinases that act as the receptor proteins mentioned above, each recognizing a different growth factor. 32 others relay the message inward from the receptor to the nucleus.
Many cancers result from having too many copies of one of the receptor proteins. Some 30 of the 58 kinds of surface receptors are implicated in some form of cancer.
25 to 30 % of breast cancers, for example, have too many copies of a receptor called epidermal growth factor receptor-2 (also called HER-2). While normal cells might have 10,000 copies, these cancer cells can have more than a million. An anticancer drug called herceptin battles breast cancer by sticking monoclonal antibodies (that is, antibodies that specialize in binding to just this protein) to these HER-2 receptors so they cant keep yelling divide.
Up to 70% of colon, prostate, lung, and head/neck cancers have excess copies of a related receptor, epidermal growth factor receptor-1 (HER-1). The monoclonal antibody C225 has succeeded in shrinking 22% of colon cancers in early clinical trials. Apparently blocking HER-1 interferes with the ability of tumor cells to recover from chemotherapy or radiation.
Signal Transduction Inhibitors. Some 15 of the 32 internal tyrosine kinases are also implicated in cancer. The trouble begins when a mutation causes one of these signal-carrying proteins to become locked into the ON position, sort of like a stuck doorbell that keeps ringing and ringing. To cure the cancer, you have to find a way to shut the bell off.
Each of the 15 signal carriers presents a different problem, as you must find a way to quiet it without knocking out all the other signal pathways the cell needs. A clear success was reported last May involving one of the internal kinases called abl.
The abl story starts in 1961, when doctors noticed that almost all patients with a rare form of white blood cell cancer called chronic myelogenous leukemia were missing a short segment of chromosome 22.
Twenty five years later, researchers David Baltimore (now President of Cal Tech) and Owen Witte of UCLA found that the break point was within the tyrosine kinase gene called abl. The break chipped off a vital section of the gene, the part that allows the signal-carrying protein to shut itself off.
In 1985 Dr. Alex Matter of Novartis and Dr. Nicholas Lydon of Amgen set out to develop inhibitor of tyrosine kinases like abl. One of the chemicals they came up with, called STI-571, proved to be just the right shape to fit into the groove of abl that does its chemistry. Like pouring cement into a piano, this totally disabled abl. STI-571, since named Gleevec, was given swift approval as a cancer therapy for this rare leukemia last month. In one trial of 54 patients, blood counts reverted to normal in more than 90% of cases.
Gleevec also inhibits two other cancer-associated tyrosine kinases. Like hounds to the hunt, researchers are looking for drugs to inhibit others.
So while we are a long way from curing cancer, our hard-won understanding of the disease in research labs around the country is beginning to suggest potential targets for therapy.
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