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Brothers in Arms Against Cancer Cancer researchers are trying to harness siblings of p53, the famous tumor-blocking protein

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He was a physician, inventor, and philosopher of some repute. Familiar with Cassandra Austen, the amateur painter and Jane’s sister? Probably not. Famous brothers and sisters often overshadow their siblings. The same thing happens in molecular families. Take p53, the tumor-suppressor protein that was named Science’s Molecule of the Year in 1993 and has been dubbed “guardian of the genome.” Few nonspecialists know that the celebrated p53 is closely related to two other proteins, p63 and p73. Yet these unheralded siblings are grabbing the attention of cancer biologists. New research suggests that p63 and p73 are fierce cancer killers that deserve equal billing with p53. Instead of a single genome protector, “there’s a family of guardians,” says cancer biologist Elsa Flores of M. D. Anderson Cancer Center in Houston, Texas. Because efforts to exploit p53 in cancer therapies haven’t yet paid off, some researchers are now looking to p73 and p63 as alternative tumor treatments. Researchers have shrunk or prevented tumors in animals by targeting p73, and the first clinical trials—attempting to use p73 to combat a hard-to-treat type of breast cancer—have already started. “It would be very attractive to find a way to activate these proteins” in people with tumors, says cancer biologist Alexander Zaika of Vanderbilt University Medical Center (VUMC) in Nashville. Strategies that capitalize on the tumor-fighting capability of the p53 family “belong in the armamentarium against cancer,” adds molecular oncologist Wafik El-Deiry of the Penn State Hershey Cancer Institute in Pennsylvania. p53, the hard target When a cell suffers DNA damage that can lead to uncontrolled growth, p53 comes to the rescue. The p53 protein can trigger DNA repair, stop the dodgy cell from dividing, or, when the damage is grievous, prompt it to commit suicide. Because p53 is so potent, cells normally keep levels of the protein low. Spurring cancer cells to produce more protein, the argument goes, could prompt tumors to self-destruct. “p53

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it, for example, by overproducing enzymes that prompt the protein’s destruction. Attacking many kinds of tumors through p53 will require pharmacological feats— restoring the gene or reshaping the malformed protein—that are tougher than the standard tactic of blocking a molecule’s unwanted function. “Many of us appreciated it [p53] would be difficult to target,” says cancer biologist Leif Ellisen of Harvard Medical School (HMS) in Boston. “Throwing a wrench into the system is much easier than fixing the system.” Yet many researchers remain confident that they will eventually overcome these obstacles. “My personal bet is still on p53,” says cancer biologist Anna Mandinova, also of HMS. But in the meantime, researchers are looking at other options, namely, p63 and p73.

YOU’VE HEARD OF CHARLES DARWIN, BUT do you know of his elder brother, Erasmus?

is a great therapeutic target,” says cancer biologist Kevin Ryan of the Beatson Insti- Band of molecular brothers tute for Cancer Research in Glasgow, U.K. Scientists discovered the p53 protein in “Its involvement in tumor suppression is 1979 but didn’t recognize its importance for cancer until 10 years later. In 1997, biolowithout question.” Scientists are pursuing a number of gists identified p73 as a molecular relative, strategies to enlist p53 in the cancer fight after discovering a DNA sequence closely (Science, 2 March 2007, p. 1211). They resembling the gene for p53. “That came have completed or are running several clini- as a bit of a surprise,” says cancer biologist cal trials for gene therapy approaches, which Gerry Melino of the University of Rome involve introducing extra copies of the p53 “Tor Vergata” in Italy. “Nobody expected gene into cancer cells. Researchers at six a protein so close to p53.” Yet researchers institutions in the United States and the reported another relative, p63, the next year. Although p53 was the first family member United Kingdom have also begun safety trials on a compound, developed by the phar- discovered, p63 and p73 are the older siblings, maceutical company Roche, that hikes p53 evolutionarily speaking. Comparisons of levels in cells by impeding the protein’s nat- their genes suggest that p53 evolved from the ural recycling. ancestral version of p63 and p73 more than So far, however, no p53-based treat- 450 million years ago. These elders have a ments have been approved for clinical use range of responsibilities. Unlike p53, p63 and in the United States. The practical difficul- p73 are essential during embryonic developties are formidable. For one thing, thanks to ment. Shaping limbs and giving the skin its a variety of mutations in p53’s gene, more layered structure are among p63’s tasks in than half of all tumors an embryo. Formation of Total PubMed Citations don’t carry a working brain regions such as the version of the protein. hippocampus and corSome harbor misshapen tex depends on p73, as mutants that are inert or does maturation of the that turn traitor and subimmune system. Both vert antitumor defenses. proteins are also necesp53 p63 p73 Even when cancer cells sary for female fertility. have a functional form of For cancer research2149 1541 ers, p63 and p73 have p53, they often neutralize 56,939

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Taking on tumors p63 and p73 battle cancer in several ways. Like their famous brother, the proteins cull cells that carry potentially cancer-causing DNA damage, activating their apoptotic, or cell suicide, pathways. Fortuitously, some

1552

TARGETING P73

cancer cells into mice and administered RETRA. The treatment cut the number 37AA Disengages p73 Shrinks tumors of tumors that sprouted in from inhibitor in mice the animals, the scientists NSC176327 Boosts p73 Kills cancer cells revealed in the Proceedproduction in culture ings of the National AcadAntisense Curtails production Curbs growth of emy of Sciences. gapmers of p73’s ∆N isoforms melanoma tumors To liberate p73 from a in mice different inhibitor that is Everolimus Increases p73 levels Trials in progress abundant in cancer cells, RETRA Separates p73 from Impedes tumor one known as iASPP, Ryan mutant p53 formation in mice and colleagues ironically On the attack. Researchers are testing antitumor compounds that rely turned to p53 for inspiration. They developed a on p73. snippet of p53, just 37 of chemotherapy already takes advantage of its nearly 400 amino acids, that in the test this ability, causing DNA damage that spurs tube separates p73 from iASPP. Dosing cancer-ridden mice with the snippet, known as p63 or p73 to kill tumor cells. Recent studies suggest that p63 also reins 37AA, shrank the rodent’s tumors, the team in metastasis, the migration of tumor cells to reported in The Journal of Clinical Investia new location in the body; that’s what usu- gation in 2007. RETRA’s effects were fairly weak, and ally kills cancer patients. In 2009 in Cell, a team led by Stefano Piccolo of the Univer- 37AA was fragile, so neither is likely to sity of Padua School of Medicine in Italy become a drug. But the importance of studrevealed that some mutant forms of p53 ies like these, says El-Deiry, is that they found in cancer cells prevent p63 from acti- show it’s possible to uncover compounds that vating two genes that curtail metastasis. And rouse p53’s siblings to attack cancer cells. last fall, in a study in Nature, Flores and col- Scientists are hunting for other molecules leagues showed that the TA isoforms of p63 that might spur p73 and p63 into action and curb metastasis through another mechanism: that could make effective drugs. El-Deiry’s boosting levels of microRNAs, RNA snip- group, for example, is in the middle of a projpets that turn down gene activity. The team ect to screen thousands of small molecules— discovered that p63’s TA isoforms increase they’ve assessed more than 70,000 so far—in production of Dicer, an enzyme that snips hopes of finding ones that switch on genes in and activates inert microRNAs. The isoforms the p53 pathway. Some of the candidates, he also raise levels of a specific microRNA, says, appear to work by activating p73. At least one group has started clinimiR-130b, that prevents cells from moving on. p63 may be the master regulator of cal trials. Medical oncologist Ingrid Mayer metastasis, says Flores, and activating it and cancer biologist Jennifer Pietenpol might increase levels of several metastasis- of VUMC are targeting a form of breast halting microRNAs by flipping on Dicer. cancer—known as triple-negative because The big question is whether drug design- the tumor cells lack three key receptor proers can capture p63’s and p73’s cancer- teins—that defies standard treatments such quelling talents. The research directed at as tamoxifen and Herceptin. The tumor cells this goal isn’t as intense or advanced as the harbor large quantities of the ∆N isoforms of work on p53, but scientists can claim some p63, which the researchers suspect prevent encouraging findings. p73 from killing the cells. Along with stanOne therapeutic strategy attempts to dard chemotherapy, patients will receive an reduce sibling rivalry in the p53 fam- existing drug, everolimus, that boosts p73 ily. The mutant p53s found in cancer cells levels by inhibiting a p73 blocker called often latch onto and neutralize p63 and p73. mTOR. The goal is to overcome p63’s interThree years ago, a research group from the ference and enable p73 to kill the tumor cells. Cleveland Clinic in Ohio screened more It’s too late for Erasmus Darwin to match than 46,000 compounds and pinpointed his brother’s fame. But these clinical trials one, named RETRA, that in test tubes and the surge of research on p63 and p73 breaks mutant p53’s embrace of p73. To suggest that the proteins are finally stepping test whether freeing p73 destroys tumors, out of the shadow of their famous sibling. the researchers then transplanted human –MITCH LESLIE Mechanism

Results

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Drug candidate

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a big advantage over their sibling: Their genes are almost never mutated in or lost from cancer cells. So p63 and p73 could in theory take over for p53 in almost all cancers, and researchers wouldn’t have to fret about restoring a lost gene or reshaping a distorted protein. That strategy will work, of course, only if p73 and p63 are tumor suppressors like their brother. But that turned out to be surprisingly tough to confirm. A standard experiment for gauging a molecule’s relevance to cancer—deleting its gene from mice— didn’t clarify the issue. Whereas mice missing p53 live to adulthood and are beset by tumors, mice lacking p63 or p73 die young from other causes, revealing little about their cancer susceptibility. Complicating the matter, although some studies found that levels of p73 or p63 fell in cancer cells, suggesting that the proteins are antitumor, other work indicated that their levels soared, implying that they foster abnormal growth. The solution to that apparent contradiction may lie in the discovery more than 10 years ago that cells don’t manufacture just one kind of each protein. They can fashion at least 12 variants, or isoforms, of the p73 protein, and at least eight isoforms of the p63 protein. Scientists divide these varieties into the longer, or TA, isoforms and the shorter, or ∆N, isoforms. In 2008, Melino, molecular geneticist Tak Mak of the University of Toronto in Canada, and colleagues engineered mice that lack all of the TA isoforms of p73 but retain the ∆N versions. The mice were prone to cancer, though they weren’t as vulnerable as rodents lacking p53. The TA isoform-deficient mice “really convinced people that these genes are acting as tumor suppressors,” says Flores. Researchers now hypothesize that in cancer, TA isoforms are generally good guys, suppressing unchecked cell growth. The ∆N isoforms, for the most part, are bad guys. They can latch on to and disable p53 and the good TA isoforms, thus aiding cancer. For example, cancer biologist Alea Mills of Cold Spring Harbor Laboratory in New York and colleagues reported in February in Cell Stem Cell that a common ∆N isoform of p63 spurs the growth of skin tumors.