• A representation of a complex between DNA and the protein p53.

    Image: Thomas Splettstoesser

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Timing is everything for cancer protein p53

Biologists find that restoring the gene for p53 can slow the spread of advanced lung tumors, but doesn’t help early-stage cancers.


Since the early 1980s, cancer researchers have known that a protein called p53 plays a critical role in protecting cells from becoming cancerous. The protein is defective in about half of all human cancers; when it functions correctly, it appears to suppress tumor formation by preventing cells with cancer-promoting mutations from reproducing.

Knowing p53’s critical role in controlling cancer, researchers have been trying to develop drugs that restore the protein’s function, in hopes of re-establishing the ability to suppress tumor growth. One such drug is now in clinical trials.

In a new study that highlights a possible limitation of such drugs, MIT cancer biologists show that restoring 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 findings, reported in the Nov. 25 issue of Nature, 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,” says David Feldser, lead author of the paper and a postdoctoral fellow at the David H. Koch Institute for Integrative Cancer Research at MIT.

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.

Guardian of the genome

The p53 protein is known to control the cell cycle, which regulates cell division. In particular, the protein stops a cell from dividing when its DNA is damaged. It then activates DNA repair systems, and if the damage proves irreparable, it instructs the cell to commit suicide.

Without p53, cells can continue dividing even after acquiring hazardous mutations. 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.

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. 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. 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.

In this study, the researchers restored normal levels of p53, but a p53-activating drug would likely generate much higher levels of the protein, says Geoffrey Wahl, a professor at the Salk Institute. With elevated p53, “it might be that you get a more significant response than what was observed here,” he says.

Wahl, who was not involved in this research, says the study sounds a cautionary note about the levels of p53 needed to effectively clear a tumor. “If you don’t have adequate p53 activation, it’s going to allow some cancer cells to escape,” he says.

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.


Topics: Biology, Cancer, Koch Institute, Research, Genetics, Howard Hughes Medical Institute (HHMI)

Comments

i like all the articales that i read about cancer.
Great find. So many questions and thoughts. Although less profitable, do we need it to be a drug, can't it just be an injection of healthy p53 proteins extracted from a healthy persons blood? Or maybe this injection could work in conjunction with the drug. You get new p53 proteins while at the same time correcting the ones that you have that are defective. This is a great advancement to medicine & health. Does this work in all types of cancers? breast, prostate, lung, etc??? It seems that it would. Worst case you stop aggressive cancers from taking life or at least taking life so quickly and painfully, giving you a chance to get treatment and surgery to get rid of the cancer. Sometimes all the patient needs is a little time and to stop the spread.
Interesting news, a new hope for the humanity, but it needs more research and funding.
That kind of approach is not possible at the moment: the deficiency of p53 lies often in the regulatory apparatus, that means that while the gene that encodes for the protein is normal, it is only kept silent by some mutation. I'll make a stupid example. Fancy we were playing a game in which there is me, you and a friend of us. The purpose is to make our friend sit down. I will pass a paper to you with a command you have to read to him loud. The command is "sit down". If I give a paper with exactly those words, you'll read it and he would sit down. Now, fancy I pass you a paper with the message "DO NOT ABSOLUTELY READ THIS MESSAGE LOUD sit down", you won't read it and our friend would still stand up. The message "sit down" is correctly written there, but you have not read it. That's what happens often to our genes. The problem is also that being this dysregulatory event definitive, you should constantly give external p53 to make it possible his function being restored. And here come a series of technical problems: 1-the size of a protein makes it impossible to be used as a drug, which is a much smaller molecule that can penetrate a cell quite more easily. 2-administering proteins in someone's blood would trigger many reactions, like being captured and destroyed by the immune system, or even allergic reactions. In fact we never use external proteins (say myoglobin we eat with meat) directly: first we destroy it into aminoacids then we rebuild it. The possible scenario this study suggests (which is great indeed) is in the end the possibility to use a small molecule like a drug to restore the self production of the p53 whose gene ("sit down") is there, but what has gone wrong is its regulation. As, according to the game example I gave you, we were able to delete with a drug the "DO NOT ABSOLUTELY READ THIS MESSAGE LOUD" part.
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