Reactivated Gene Shrinks Tumors

Now, for the first time, researchers have demonstrated that re-activating one of those genes in mice can cause tumors to shrink or disappear.

The study provides evidence that the tumor-suppressor gene p53 is a promising target for human cancer drugs. "If we can find drugs that restore p53 function in human tumors in which this pathway is blocked, they may be effective cancer treatments,” said Dr. David Kirsch, one of the lead co-authors of the study, from the Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) Center for Cancer Research and Harvard Medical School (Boston, MA, USA).

The findings of the research were published in the January 24, 2007, online edition of the journal Nature. The study was conducted in the MIT laboratory of Dr. Tyler Jacks, director of the Center for Cancer Research. p53 has long been known to play a crucial role in the development of many tumors--it is mutated in more than 50% of human cancers. Researchers have identified a few compounds that restore p53 function, but until now, it has not been known whether such activity would actually reverse tumor growth in primary tumors.

This new MIT study revealed that re-activating p53 in mouse tumors dramatically reduces the size of the tumors, in some cases by 100%. "This study provides critical genetic evidence that continuous repression of a tumor-suppressor gene is required for a tumor to survive,” said Dr. Andrea Ventura, an Italian postdoctoral associate in the Center for Cancer Research and first author of the study.

In healthy cells, p53 controls the cell cycle; meaning when functioning correctly, it activates DNA repair mechanisms and prevents cells with damaged DNA from dividing. If DNA damage is beyond repair, p53 induces the cell to destroy itself by undergoing apoptosis, or programmed cell death.
When p53 is inactivated by mutation or deletion, cells are much more likely to become cancerous, because they will divide uncontrollably even when DNA is damaged.

In this study, the researchers utilized modified mice that had the gene for p53 inactivated. But they also included a genetic "switch” that allowed the researchers to turn p53 back on after tumors developed. Once the switch was activated, p53 appeared in the tumor cells and the most of the tumors shrank between 40 and 100%.

The researchers evaluated two different types of cancer--lymphomas and sarcomas. In lymphomas, the cancer cells underwent apoptosis within one or two days of the p53 reactivation. By contrast, sarcomas (which affect connective tissues) did not undergo apoptosis but went into a state of senescence, or no growth. Those tumors took a longer time to shrink but the senescent tumor cells were eventually cleared away.

The researchers have not determined why these two cancers are affected in different ways, but they are now trying to understand why by identifying the other genes that are activated in each type of tumor when p53 turns back on. The study also revealed that activating p53 has no debilitating effects in healthy cells. The researchers had been concerned that p53 would destroy healthy cells because it had never been expressed in those cells. "This means you can design drugs that restore p53 and you don't have to worry too much about toxic side effects,” said Dr. Ventura.

Potential therapeutic approaches to trigger p53 in human cancer cells include small molecules that restore mutated p53 proteins to a functional state, as well as gene therapy techniques that introduce a new copy of the p53 gene into tumor cells. One class of potential drugs now under investigation, known as nutlins, act by interfering with MDM2, an enzyme that keeps p53 levels low.

In follow-up studies, the MIT researchers are looking at other types of cancer, such as epithelial cancer, in their mouse model, and they plan to see if the same approach will also work for tumor suppressors other than p53.




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