Tumors shrink when p53 restored

Restoring p53 function in mouse tumors in vivo causes tumors to shrink, according to three new reports published in Nature and Cell. The studies, two of which were published this week, demonstrate that tumor maintenance requires continued absence of p53 activity, and suggest that restoring p53 may shrink human cancers, as well. However, as with most cancer therapies, the tumor finds a way around the body's defenses, and in one study, tumors returned after they had regressed following p53 restoration."All three studies all have the same fundamental observation: When you reactivate p53 the tumors all regress, and this is good news because it suggests that targeting mechanisms that reactivate p53 function would be a worthy point of attack for cancer drugs," Ron DePinho, American Cancer Society Research Professor at Harvard Medical School, told The Scientist. DePinho wrote a News & Views article in Nature about the three studies, and was not involved with any of the research. P53 is a transcription factor and tumor suppressor protein that halts cell growth in response to DNA damage, and p53 lesions are the most commonly observed mutations in human cancers. These studies, led by Tyler Jacks at the Massachusetts Institute of Technology, Scott Lowe at Cold Spring Harbor Laboratory, and Gerard Evan at the University of California, San Francisco, investigated whether the inactivation of p53 is only necessary early on in a tumor's development, or is required throughout the tumor's lifetime."We know that p53 mutation is important in the development of many cancers, but from what had been done previously, the possibility existed that loss of p53 facilitated other changes, and that once those other changes occurred, then the absence of p53 could be irrelevant," Jacks told The Scientist. "That possibility existed, and that was the motivation of this study."Using tetracycline-inducible RNA interference (Lowe), an estrogen-responsive p53 (Evan), or an estrogen-responsive Cre recombinase (Jacks), the three teams built mice that, as p53 nulls, spontaneously produce tumors, but could activate p53 in response to drug treatment. In all three studies, p53 restoration led to rapid p53 activation and tumor regression. Evan published his findings Dec. 29 in Cell; Jacks' and Lowe's findings are published this week in Nature. Collectively, the studies observed p53-induced regression in lymphomas, hepatocarcinomas, and sarcomas. Precisely why the tumors shrank differed by type: Lymphomas regressed via apoptosis, while the sarcomas and hepatocarcinomas were cleared by the innate immune system. This latter observation -- that the innate immune system plays a role in clearing tumors -- was "completely unexpected," said Lowe. "We thought p53 would kill the cells, but instead, p53 stops the cells from growing and then the cells signal the innate immune system.""I think it's really exciting, outstanding work," said Dean Felsher, an oncologist and associate professor of medicine and pathology at the Stanford University School of Medicine, who was not involved in the research. In 1999, Felsher helped to establish that oncogenes like Myc are also required for tumor maintenance -- an idea that forms the basis of anti-oncogenic drugs like Gleevec. Felsher called the experiments "very soundly done," but said their novelty was in the approach more than in the results. "People had fixed p53 in cell lines. But the way they did it in an actual tumor was really elegant and particularly convincing." Still, he said it will be difficult to translate these mouse results into clinical benefits. "I think everyone's impression is that it will be much harder to cure human tumors than mice [tumors], because so far that's been the experience."Several pharmaceutical options for restoring p53 activity are in development, according to DePinho, including small molecules that could cause mutant p53 to fold properly, drugs to block p53's upstream inhibitor mdm2, and methyltransferase inhibitors to reactivate p19-Arf, an upstream activator of p53. Even in mice, tumors can quickly adapt to the restored p53. Following the initial tumor regression, all the mice in Evan's study relapsed, either via loss of p53 or p19-Arf. He suggested that combining therapies -- for instance, reactivating p53 while simultaneously deactivating an oncogene -- could circumvent this problem. "The bottom line," said Evan, "is evolution is handing us a few benefits. If by human artifice we can knock these tumors on their heads, our bodies have ways to clean up the mess. It wasn't expected, but it's incredibly encouraging."Jeffrey M. Perkel jperkel@the-scientist.comLinks within this articleM.L. Phillips, "Cell death unnecessary for tumor suppression," The Scientist, Sept. 6, 2006. http://www.the-scientist.com/news/display/24625/Ronald A. DePinho http://www.hms.harvard.edu/dms/bbs/fac/depinho.htmlN.E. Sharpless, R.A. DePinho, "Gone but not forgotten," Nature, advance online publication, DOI:10.1038/nature05567, Jan. 24, 2007. http://www.nature.comTyler Jacks http://web.mit.edu/jacks-lab/index.htmlScott Lowe http://www.cshl.edu/public/SCIENCE/lowe.htmlGerard Evan http://cancer.ucsf.edu/evan/index.phpC.P. Martins, L. Brown-Swigart, G.I. Evan, "Modeling the therapeutic efficacy of p53 restoration in tumors," Cell, 127:1323 - 34, Dec. 29, 2006. http://www.cell.com/content/article/abstract?uid=PIIS0092867406015972A. Ventura et al., "Restoration of p53 function leads to tumour regression in vivo," Nature, advance online publication, DOI:10.1038/nature05541, Jan. 24, 2007. W. Xue et al., "Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas," Nature, advance online publication, DOI:10.1038/nature05529, Jan. 24, 2007. http://www.nature.com/A. Constans, "The innate immunity adapter list grows," The Scientist, July 18, 2005. http://www.the-scientist.com/article/display/15622/Dean Felsher http://med.stanford.edu/labs/dean_felsher/D.W. Felsher, J.M. Bishop, "Reversible tumorigenesis by MYC in hematopoietic lineages," Mol Cell, 4:199 - 207, 1999. http://www.the-scientist.com/pubmed/10488335

Tumors shrink when p53 restored

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