Stanford University scientists say they've reversed bone cancer in mice by giving the animals a short course of a drug to temporarily shut down a potent tumor gene. Intriguingly, the drug continued to work even after it was halted, having somehow reprogrammed the cancerous cells into killing themselves rather than return to their malignant ways.
The findings, which appear today in the journal Science, suggest that some tumors may become desperately "addicted" to the influence of their genes. Muzzling that instruction could be enough to suppress abnormal cell growth."The same gene that was responsible for the cancer can be the thing that kills the cancer," says Dr. Dean Felsher, a Stanford oncologist and a co-author of the study.
Similarly, the study also hints that certain cancers may be treated with relatively brief periods of drug therapy, followed perhaps by periodic booster doses to mop up any residual renegade cells. Scientists have feared that people with cancer genes may be perpetually at risk of tumors.
Why oncogenes appear to have this "live by the sword, die by the sword" trait isn't clear, Felsher says. It may be that cancer is a state that requires a specific confluence of genetic defects that are highly sensitive to context. Once interrupted, re-creating that state isn't possible, just as trying to put Humpty Dumpty back together again eluded the kingdom. "When you turn off an oncogene, the cells really change their context," he says.
Felsher and his colleagues created a strain of mice with a hyperactive cancer gene called MYC, which normally regulates hundreds of other genes involved in cell growth and proliferation. When over-expressed by a factor of five or 10, this gene is linked to a wide range of cancers, including tumors of the bone, breast and prostate.
Building on the work of a German scientist, Felsher's group engineered the MYC genes to cause bone tumors, but only in the absence of the antibiotic doxycycline.
When the mice were treated with the drug -- which, incidentally, may have anti-cancer properties at high doses -- the abnormal bone cells stopped expressing MYC. The tumors started to subside, and the bone cells began forming into healthy skeleton.
Felsher's group next tried to reactivate the errant gene by suspending the antibiotic signal. Instead of reviving the cancers, nearly all of the bone cells expressing the gene committed suicide, or apoptosis.
Mice whose MYC gene was disabled for 10 days survived for more than three months without tumors, up to four times longer than the untreated rodents. Two of the 12 animals in this group lived for five months. Although bone tumors recurred in some of the treated animals, they sank into remission after another round of doxycycline.
Even though the study was conducted in mice, experts say the findings could apply to people, too. MYC is active in many human cancers. However, targeting the gene may not be universally effective because its role varies by tumor type, promoting abnormal cell growth for some cells but destabilizing the genes of others, Felsher says.
Dr. I Bernard Weinstein, a Columbia University genetics expert, says the findings support earlier work that shows some cancer cells are addicted to their tumor genes -- and that muting these genes can shut down abnormal growth. The new drug Gleevec is such a therapy, attacking a wayward gene in blood cells called Bcr-Abl.
In theory, says Weinstein, author of a commentary accompanying the journal article, scientists could use DNA-reading microchips to screen tumors for overactive genes that might be targets for correction.
"The key is to find in a given tumor which oncogenes are overactive and to which of them the tumor is addicted so that they really need that over-expression -- and then to target that oncogene by developing a drug or antibody which will inhibit its function," he says.
However, Weinstein says doctors need to be cautious here. Cancers, like pathogens, can develop resistance to therapies that are too specifically tailored. If a drug affects one oncogene, others might rise up and take its place. Likewise, cells that weren't killed by the treatment might then overrun the patient.
Some evidence suggests a small fraction of leukemia patients may be developing resistance to Gleevec. "We are seeing escape from oncogene addiction in a subset of patients," he says.
Ultimately, Weinstein says, taking aim at oncogenes "is not in itself a panacea for treatment. It is a very useful Achilles' heel to attack, but we may still need other drugs."
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