Howard Hughes Medical Institute researchers have developed two strategies to reactivate the p53 gene in mice, causing blood, bone and liver tumors to self destruct. The p53 protein is called the “guardian of the genome” because it triggers the suicide of cells with damaged DNA.
Inactivation of p53 can set the stage for the development of different types of cancer. The researchers' findings show for the first time that inactivating the p53 gene is necessary for maintaining tumors. While the researchers caution that cancers can mutate to circumvent p53 reactivation, they believe their findings offer ideas for new approaches to cancer therapy.
The research was carried out independently by two Howard Hughes Medical Institute (HHMI) research teams led by Tyler Jacks at the Massachusetts Institute of Technology and Scott Lowe at Cold Spring Harbor Laboratory. Both papers were published online January 24, 2007, in advance online publication articles in the journal Nature.
The techniques the teams used to reactivate the p53 gene could not be used therapeutically in humans because they genetically engineered the mice to have their p53 genes controllable with drugs.
To reactivate p53, Lowe and his colleagues used a genetic technique they had developed to induce an aggressive form of liver cancer in mice. Although they had inactivated p53 in the mice, they genetically engineered the mice so that they could reverse p53 inactivation by giving the animals the antibiotic doxycycline. They suppressed p53 protein levels by using RNA interference (RNAi) that had been modified so that RNAi could be switched off by the antibiotic. The RNA interference technology was developed in collaboration with HHMI investigator Gregory Hannon at Cold Spring Harbor Laboratory.
When the researchers reactivated p53 in the mice they found that the liver tumors completely disappeared. “This was quite surprising,” said Lowe. “We were working with a very advanced, aggressive tumor, but when we reestablished p53, not only did it stop growing, it went away.
The most obvious way to try to duplicate this result in humans would be to send in p53 genes in some sort of gene therapy delivery package. But we lack the technologies needed to do that. Gene therapy delivery is a hard problem.
The way that p53 activation stopped the cancers was surprising. It made cells go into a senescent state rather than to commit suicide. But once in the senescent state the immune system in the mice attacked these cells.
“But the second surprise—and perhaps the more scientifically interesting one—was why the tumor went away,” said Lowe. “We expected the tumor cells to undergo programmed cell death, or apoptosis. But instead, we saw evidence for a very different process that p53 also regulates—senescence, or growth arrest. What really excited us was evidence that this senescence somehow triggered the innate immune system to kill the tumor cells.” Involvement of the innate immune system suggests there may be an unknown mechanism by which cancers can trigger the immune system, he said. Lowe and his colleagues are now exploring how the innate immune system might be enlisted against cancer.
How do cancer cells suppress the immune system to prevent it from attacking them? These mice make for a good research model to try to figure out how cancer cells protect themselves from immune attack. Once scientists know how that works they can develop therapies that'll basically block the immune suppression mechanisms used by cancer cells. Then cancer vaccines would become far more potent.
For some types of cancer the gene for p53 might still be intact but deactivated. A drug might be able to reactivate it. But in other types of cancer p53 is probably so mutated that it can't be reactivated. Delivery of replacement genetic material might be the only solution. But that approach runs up against the problem of how to deliver a replacement gene into every single cancer cell in a person's body.
Genetically engineered copies of p53 could find use in human stem cell therapies and in the development of replacement organs. Replacement cells could have not only normal copies of p53 but also additional copies which will activate only in the presence of a particular drug. That way if cells ever go cancerous due to mutations in regular p53 genes a back-up set of p53 genes could get activated by a prescription antibiotic or some other drug. Think of such genetically engineered p53 genes as akin to emergency brakes in cars. If your main cancer brakes give way additional sets of cellular brakes could get turned on.
|Share |||Randall Parker, 2007 January 24 08:52 PM Biotech Cancer|