CAMBRIDGE, Mass.—A team of MIT cancer biologists has found that restoring the protein p53's function in mice with lung cancer has no effect early in tumor development, but restoring the function later on could prevent more advanced tumors from spreading throughout the body.
The results of the team's study were published in the Nov. 25 issue of Nature.
"The take-home message from this study really has to do with how you would use drugs once they are ready for deployment," says David Feldser, lead author of the paper and a postdoctoral fellow at the David H. Koch Institute for Integrative Cancer Research at MIT. "In abstract ways, I think it could educate drug discovery. In reality, I think it will educate drug utilization."
Cancer researchers have known since the 1980s that p53 plays a critical role in protecting cells from becoming cancerous.
Feldser points out that p53 is defective in about half of all human cancers, and when it functions correctly, it appears to suppress tumor formation by preventing cells with cancer-promoting mutations from reproducing.
"Even within cancer types, about half of all tumors have p53 mutations when they become clinically discovered," he notes. "I think the relevance is quite high."
Moreover, Feldser explains that only in rare human genetic diseases is an individual born with a p53 mutation. Those individuals do not have cancer when they are born and it takes another mutation for the cancer to manifest itself in the cells.
Knowing p53's critical role in controlling cancer, researchers have been trying to develop drugs that restore the protein's function, in hopes of reestablishing the ability to suppress tumor growth. One such drug is now in clinical trials.
The findings of the MIT study suggest that drugs that restore p53 function could help prevent aggressive lung cancers from metastasizing, though they might spare benign tumor cells that could later turn aggressive.
"Even if you clear the malignant cells, you're still left with benign cells harboring the p53 mutation," Feldser points out.
However, such drugs are still worth pursuing because they could prolong the life of the patient, says Feldser, who works in the lab of Koch Institute Director Tyler Jacks, senior author of the paper. The research was funded by the Howard Hughes Medical Institute.
P53 is known to control the cell cycle, which regulates cell division.
"The protein stops a cell from dividing when its DNA is damaged. P53 then activates DNA repair systems, and if the damage proves irreparable, it instructs the cell to commit suicide," Feldser notes.
Without p53, cells can continue dividing even after acquiring hazardous mutations.
Feldser notes that eventually, after a cell accumulates enough mutations, it becomes cancerous. "Cancer biologists believe that sustained inactivation of p53 and other tumor suppressors is necessary for cancers to become advanced," he says.
In the new Nature study, the MIT researchers studied mice that are genetically engineered to develop lung tumors shortly after birth. Those mice also have an inactive form of the p53 gene, but the gene includes a genetic "switch" that allows the researchers to turn it back on after tumors develop.
At first, the researchers turned on p53 in mice that were four weeks old and had developed tumors known as adenomas, which are benign. To their surprise, restoring p53 had no effect on the tumors.
Next they turned on p53 in another group of tumor-prone mice, but they waited until the mice were 10 weeks old.
Feldser explains that at this point, their tumors had progressed to adenocarcinomas, a malignant type of cancer. In these mice, turning on p53 cleared the malignant cells, but left behind cells that had not become malignant.
"This suggests that the p53 signaling pathway is recruited only when there is a lot of activity from other cancer genes," he says, "In benign tumors, there is not enough activity to engage the p53 system, so restoring it has no effect on those tumors."
In the malignant tumor cells, reactivated p53 eliminates cells with too much activity in a signaling pathway involving mitogen-activated protein kinase (MAPK), which is often overactive in cancer cells, leading to uncontrolled growth.
"It does seem to be a common feature of p53 that it seems to mutate later in stages of most human cancers," Feldser notes. "We don't really understand why it is mutated late, rather than early. I think this sheds some light on that. We found that when we turned p53 on, early-stage tumors didn't seem to care. In later stage, those tumors did seem to care. An early-stage tumor doesn't have a selective pressure to lose it at that point. Once it acquires some other mutation or some other environmental situation associated with advanced cancer, that it now needs to lose p53."
The MIT researchers are now looking for drugs that reactivate mutant forms of p53, and also plan to study whether tumors that have metastasized would be vulnerable to p53 restoration.
"We'd like to extend our findings beyond this one transition from benign to malignant tumors to try to understand what p53 does when you turn it back on and in metastatic tumors and in tumors with metastatic potential," Feldser says. "We'd also like to explore the possibility of discovering drugs that can fix mutations in p53 and lead to somewhat normal function of a mutated form of p53."
As the team moves forward with its research, there are some clearly defined benchmarks that can serve as true measures of continued success for their efforts.
"I think as long as we are making important biologically discoveries and headway in the discovery of small molecules that can have therapeutic benefits for anyone with p53 mutations in their tumors, I think that would be extremely successful," Feldser concludes.
