Pagano back to coach Colts after cancer treatment

INDIANAPOLIS (AP) — Chuck Pagano stepped to the podium Monday, hugged his team owner, thanked his family for its support and wiped a tear from his eye.

He might, finally, turn out the lights in his office, too.

Nearly three months to the day after being diagnosed with leukemia, the Colts' first-year coach returned to a team eager to reunite with a boss healthy enough to go back to work.

"I told you my best day of my life was July 1, 1989," Pagano said, referring to his wedding date. "Today was No. 2. Getting to pull up, drive in, get out of my car, the key fob still worked. I was beginning to question whether it would or not. When I asked for Bruce to take over, I asked for him to kick some you-know-what and to do great. Damn Bruce, you had to go and win nine games? Tough act to follow. Tough act to follow. Best in the history of the NFL. That's what I have to come back to."

The comment turned tears into the laughter everyone expected on such a festive occasion.

For Pagano and the Colts, Monday morning was as precious as anyone could have imagined when Pagano took an indefinite leave to face the biggest opponent of his life, cancer.

In his absence, all the Colts was win nine of 12 games, make a historic turnaround and clinch a playoff spot all before Sunday's regular-season finale against Houston, which they pegged as the day they hoped to have Pagano back. If all goes well at practice this week, Pagano will be on the sideline for the first time since a Week 3 loss to Jacksonville.

Pagano endured three rounds of chemotherapy to put his cancer in remission.

That Pagano's return came less than 24 hours after Indy (10-5) locked up the No. 5 seed in the AFC and the day before Christmas seemed fitting, too.

"I know Chuck is ready for this challenge. In speaking to his doctor multiple times, I know that the time is right for him to grab the reins, get the head coaching cap on and begin the journey," owner Jim Irsay said. "It's been a miraculous story. It really is a book. It's a fairytale. It's a Hollywood script. It's all those things but it's real."

The reality is that he's returning to a vastly different team than the one he turned over to Arians, his long-time friend and first assistant coaching hire.

Back then, the Colts were 1-2 and most of the so-called experts had written them off as one of the league's worst teams. Now, they're ready to show the football world that they can be just as successful under Pagano as they were under Arians, who tied the NFL record for wins after a midseason coaching change.

Pagano also has changed.

The neatly-trimmed salt-and-pepper hair and trademark goatee that were missing in November have slowly returned, and the thinner man who appeared to be catching his breath during a postgame speech in early November, looked and sounded as good as ever Monday.

He repeatedly thanked fans for their prayers and letters, the organization and his family for their unwavering help and promised to provide comfort and support to other people who are facing similar fights. During one poignant moment that nearly brought out tears again, Pagano even recounted a letter sent to him by a 9-year-old child who suggested he suck on ice chips and strawberry Popsicles in the hospital and advised him to be nice to the nurses regardless of how he felt — and he never even paused.

"I feel great, my weight is back, my energy is back and again, it's just a blessing to be back here," Pagano said.

In the minds of Colts players and coaches, Pagano never really left.

He continually watched practice tape and game film on his computer, used phone calls and text messages to regularly communicate with players and occasionally delivered a pregame or postgame speech to his team.

"He texted me and called me so much, it was like he was standing there in my face every day," said receiver Reggie Wayne, who has been friends with Pagano since the two were working together at the University of Miami.

But the Colts found plenty of other ways to keep Pagano's battle in the forefront.

They began a fundraising campaign for leukemia research, calling it Chuckstrong. Players had stickers with the initials CP on their locker room nameplates, and Arians wore an orange ribbon on his baseball cap during games. Orange is the symbolic color for leukemia. At one point, nearly three dozen players shaved their heads to show their ailing coach they were with him.

That's not all.

Arians and first-year general manager Ryan Grigson decided to leave the lights on in Pagano's office until he returned. Pagano noted the team even installed plastic clips to make sure those lights were not mistakenly turned off while he was gone. Those clips were removed when Pagano arrived Monday morning.

And Arians said nobody sat in the front seat of the team bus.

"He's always been our head coach," Arians said.

So after getting medical clearance from his oncologist, Dr. Larry Cripe, to return with no restrictions, Pagano couldn't wait to get to the office Monday morning.

Arians arrived at 7 a.m., three hours early for the scheduled team meeting. By then, Pagano had already driven past the inflatable Colts player with the words "Welcome Back Chuck" printed on its chest and was back in his office preparing for the Texans.

Players showed up a couple of hours later, and when the torch was passed from Arians back to Pagano, players gave their returning coach a standing ovation that Wayne said was well-deserved.

All Pagano wants to do now is emulate the success Arians and his players have had this season.

"I asked him (Arians) if he would lead this team and this ballclub and this organization and take over the reins," Pagano said. "What a masterful, masterful job you did Bruce. You carried the torch and all you went out and did was win nine ballgames. You got us our 10th win yesterday and you got us into the playoffs. You did it with dignity and you did it with class. You're everything that I always knew you were and more."

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Philippine Law Forbids Abductions by Military

MANILA — The Philippines has enacted a law aimed at stopping the military and police officers from abducting people suspected of antigovernment activity, one of the ugly legacies of years of dictatorship.

The law, which President Benigno S. Aquino III signed late Friday, makes the “arrest, detention, abduction or any other form of deprivation of liberty committed by agents of the state” punishable by life in prison. Congress passed the legislation in October.

Human Rights Watch said the law was “a major milestone in ending this horrific human rights violation.” It was the first major human rights legislation signed by Mr. Aquino, who campaigned on promises of a better human rights climate. Many rights groups say his record since his election in 2010 has been mixed.

The kidnapping of political opponents by the security forces in the Philippines is a legacy of martial law, imposed in the 1970s by the dictator Ferdinand E. Marcos. During that period, political opponents were abducted, tortured and sometimes killed.

Such actions continue today on a smaller scale, despite the restoration of democracy in 1986, according to rights advocates. The organization Families of Victims of Involuntary Disappearance, based in Manila, says that since 1985 more than 2,200 people have disappeared at the hands of the security forces or others linked to the government.

“It is a way for the authorities to short-circuit our laws and Constitution,” said Carlos Isagani Zarate, a vice president of the National Union of Peoples’ Lawyers, which represents people who say they have been abducted by the military. “If they suspect someone is part of an underground organization but they don’t think the case will prosper in court, they abduct them.”

“In a lot of the cases, the victims are innocent civilians who are suspected of having links to underground groups,” Mr. Zarate said.

Under Mr. Aquino — the son of an opposition politician who was assassinated during Mr. Marcos’s rule and former President Corazon C. Aquino, who led the popular uprising that drove Mr. Marcos from power — there have been 17 documented cases of forced disappearances, according to Mary Aileen D. Bacalso, secretary general of the Asian Federation Against Involuntary Disappearances. That, however, is a steep decline from the more than 300 cases alleged during the administration of his predecessor, Gloria Macapagal Arroyo.

“The number of cases has decreased, but we cannot tolerate even one forced disappearance,” Ms. Bacalso said. “The cases continue despite the pronouncements of the administration in support of human rights.”

One notorious case from the previous administration that the Justice Department has yet to resolve is that of Jovito Palparan, a retired general who was given the nickname “The Butcher” during his more than two decades of military service. He was indicted in December 2011 in connection with the abduction in 2006 of two women who were university students and activists for leftist groups. According to a statement filed in court by the prosecution, the women were kept chained in a barracks and were periodically tortured and sexually assaulted by soldiers under General Palparan’s command.

“The girls narrated the circumstances of their abduction to our witness,” said Edre Olalia, a lawyer for the victims’ families. “He saw them being tortured in a restroom. It was a horrible account of physical and sexual abuse.”

Despite a nationwide manhunt, and the offer of a large reward for his capture, General Palparan is still at large.

“It is immensely difficult to prosecute these kinds of cases,” Mr. Olalia said. “I don’t think this new law alone will make prosecution any easier. There must be a strong demonstration to the security forces that they can no longer get away with this. So far, the administration has not done that.”

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British retailers start online sales early

LONDON (Reuters) – British retailers have brought forward their Christmas clearance sales online in the hope that shoppers will log on to buy bargains and offset lackluster spending in stores.

Marks & Spencer launched its sale online at midday on Monday, it said on its website, while department store John Lewis said it would cut online prices when its stores close at 1700 GMT. Debenhams has already started its online sale.

Retailers in recent years have started sales online on Christmas Day, ahead of the clearances in stores from Boxing Day, but are increasingly launching their online offers before Christmas after delivery deadlines for the day have passed.

Hard-pressed shoppers have been leaving it later to buy presents in the hope that retailers would slash prices, the British Retail Consortium said.

It was forecasting that 5 billion pounds ($ 8.1 billion) would be spent in the shops on Saturday and Sunday combined, the last weekend before Christmas.

Richard Dodd, the BRC’s head of Media and Campaigns, said weekend trading had met expectations.

“Christmas, ultimately once all the final sums are done, will turn out to be acceptable but not exceptional,” he said.

He said the sector expected a modest increase in cash spending against a year go, but not necessarily any significant increase in real terms once inflation was stripped out.

Many British families‘ budgets are stretched, according to a survey from Markit that showed the biggest deterioration in household finances for seven months.

Analyst Howard Archer at IHS Global Insight said the weakening in household finances could not come at a worse time for retailers, and it highlighted why many people appeared to have been careful in their Christmas shopping this year.

“The suspicion has to be that consumers will be especially keen to take advantage of genuine major bargains in the sales to acquire items that they cannot otherwise afford or are reluctant to make at the moment,” he said.

“However, we suspect that people will likely to be more careful in buying – or reluctant to buy – items that they don’t really want or need in the sales.”

($ 1 = 0.6180 British pounds)

(Reporting by Paul Sandle; Editing by Louise Heavens)

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Colts recovering coach returns to team facility

INDIANAPOLIS (AP) — Chuck Pagano was back at work Monday morning.

Three months after taking an indefinite leave to battle leukemia, the Colts' coach was scheduled to meet with players, coaches and reporters as he retook the reins from interim coach Bruce Arians.

When Pagano arrived at the team headquarters, he drove past an inflatable Colts player to the side of the driveway with a simple message across the chest "Welcome Back Chuck." The sign usually reads "Beat," plus whichever team the Colts play next.

Indianapolis (10-5) has been waiting months for this day, and last week Arians called Pagano's impending return the best Christmas gift the team could get.

Pagano began the first of three rounds of chemotherapy Sept. 26, after the team completed its final practice during a bye week.

When the Colts returned to their practice facility Oct. 1, they were told Pagano had cancer and was taking an indefinite leave.

Arians, a prostate cancer survivor, immediately established the goal: Play long enough so Pagano could return to the sideline this season.

If all goes well at practice this week, Pagano will likely be on the sideline calling the shots Sunday against AFC South champion Houston in the regular-season finale. It would be the first time Pagano has been making game-day decisions since Jacksonville scored a last-minute touchdown on an 80-yard TD pass in Week 3, handing Indy it's only home loss this season.

Under Arians, the Colts did better than anyone expected.

When players arrived at training camp in August, they handed out T-shirts that showed where the so-called experts figured they would finish this season: The NFL's worst team again.

But with Sunday's 20-13 victory at Kansas City, Indy clinched its first playoff spot of the post-Peyton Manning era and Arians tied the league record for most wins after a midseason coaching change (nine). Indy is the fourth team in league history to win two or fewer games one season and 10 or more the next and became the second team in league history to lose 14 or more games one season and win 10 or more the next — joining the 2008 Miami Dolphins.

Pagano was never far from the Colts' thoughts while he was out.

He was in contact with players and coaches primarily through phone calls and text messages, watched tapes of practices and games on his computer, attended three home games and sometimes showed up at the team complex. He occasionally gave pregame or postgame speeches throughout his recovery.

On Nov. 5, Pagano's oncologist, Dr. Larry Cripe, said the illness was in complete remission, though Pagano still had to complete two more rounds of chemotherapy. The last round ended the first week of December. Last Thursday, Cripe said he gave Pagano medical clearance to return to the team. Cripe said he was putting no restrictions on what Pagano could do, only that he advised Pagano, as he does with other patients, to scale things back if necessary.

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Risks: Pedestrian Accidents More Deadly in Men

More than twice as many men as women die in pedestrian-vehicle accidents. Now researchers have partly determined why.

Writing online last month in the journal Injury Prevention, investigators considered the contribution of three factors: distance walked, number of accidents and fatalities per collision.

Researchers using data from a variety of sources found that men and women walk similar distances and that men are involved in slightly more accidents per mile. Only 1 percent of the difference in death rates is attributable to distance walked, they found, and 20 percent to an increased number of accidents among men.

The rest — 79 percent of the variation — owes to the fact that when there is a collision, men die at roughly twice the rate of women. According to the National Highway Traffic Safety Administration, 4,280 pedestrians died in traffic accidents in 2010, and 2,946 — 69 percent — were men.

Why? No one knows, but the lead author, Dr. Motao Zhu, an assistant professor of epidemiology at West Virginia University, suggested two possibilities: “Maybe males are more likely to cross roads with speed limits higher than 50 miles per hour,” he said. “Also, males may be more likely to be impaired by alcohol and drugs. Most people know it’s not safe to drive drunk, but it’s not safe to walk drunk either.”

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E-Book Price War Has Yet to Arrive

Thor Swift for The New York Times

A Google e-reader is displayed at a bookstore. Sales of e-books for the devices have slowed this year.

Right about now, just as millions of e-readers and tablets are being slipped under Christmas trees, there was supposed to be a ferocious price war over e-books.

Last spring, the Justice Department sued five major publishers and Apple on e-book price-fixing charges. The case was a major victory for Amazon, and afterward there were widespread expectations — fueled by Amazon — that the price of e-books would plunge.

The most extreme outcome went like this: Digital versions of big books selling for $9.99 or less would give Amazon complete domination over the e-book market. As sales zoomed upward, even greater numbers of consumers would abandon physical books. The major publishers and traditional bookstores were contemplating a future that would pass them by.

But doomsday has not arrived, at least not yet. As four of the publishers have entered into settlements with regulators and revised the way they sell e-books, prices have selectively fallen but not as broadly or drastically as anticipated.

The $10 floor that publishers fought so hard to maintain for popular new novels is largely intact. Amazon, for instance, is selling Michael Connelly’s new mystery, “The Black Box,” for $12.74. New best sellers by David Baldacci and James Patterson cost just over $11.

One big reason for the lack of fireworks is that the triumph of e-books over their physical brethren is not happening quite as fast as forecast.

“The e-book market isn’t growing at the caffeinated level it was,” said Michael Norris, a Simba Information analyst who follows the publishing industry. “Even retailers like Amazon have to be wondering, how far can we go — or should we go — to make our prices lower than the other guys if it’s not helping us with market share?”

Adult e-book sales through August were up 34 percent from 2011, an impressive rate of growth if you forget that sales have doubled every year for the last four years. And there have been more recent signs of a market pausing for breath.

Macmillan, the only publisher that has not settled with the Justice Department, said last week as part of a statement from John Sargent, its chief executive, that “our e-book business has been softer of late, particularly for the last few weeks, even as the number of reading devices continues to grow.” His laconic conclusion: “Interesting.”

Mr. Norris said Simba, which regularly surveys e-book buyers, has been noticing what it calls “commitment to content” issues.

“A lot of these e-book consumers aren’t behaving like lab rats at a feeder bar,” the analyst said. “We have found that at any given time about a third of e-book users haven’t bought a single title in the last 12 months. I have a feeling it is the digital equivalent of the ‘overloaded night stand’ effect; someone isn’t going to buy any more books until they make a dent in reading the ones they have already acquired.”

Another, more counterintuitive possibility is that the 2011 demise of Borders, the second-biggest chain, dealt a surprising blow to the e-book industry. Readers could no longer see what they wanted to go home and order. “The print industry has been aiding and assisting the e-book industry since the beginning,” Mr. Norris said.

It is possible that Amazon, which controls about 60 percent of the e-book market, is merely holding back with price cuts for the right moment.

The next few weeks are when e-book sales traditionally take a big jump, as all those newly received devices are loaded up with content.

Amazon declined to comment beyond saying, “We have lowered prices for customers from the prices publishers set on a broad assortment of Kindle books.” Barnes & Noble declined to comment on its pricing strategy.

The question of the proper price for e-books has shadowed the industry ever since Amazon introduced the Kindle in late 2007 and created the first truly popular portable reading device. Amazon had a natural impulse to build a market and was an aggressive retailer in any case, so it took best sellers that cost $25 in independent bookstores and sold them for $9.99 as e-books. Consumers liked that. E-book adoption soared.

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Syrian Airstrikes Reportedly Kill Dozens at Bakery

BEIRUT — A Syrian warplane was reported to have conducted airstrikes that killed dozens of people lined up for bread at a bakery in the central town of Hilfaya, according to anti-government activists in the area.

The attack, and its toll, could not immediately be confirmed. A local activist in the town named Samer said he ran to the bakery soon after heard a warplane, then bombs and finally the sound of ambulances. “There were bodies everywhere,” he said, adding that he saw tens of bodies taken away in cars.

Photographs he said he took at the bakery showed bodies in a heap on a bloody sidewalk, outside a low-slung building blackened with soot and stained with patches of blood, high on the walls. Amateur video showing what activists said was the aftermath of the attack showed roughly a dozen people lying on the ground, some wounded and several apparently dead.

In one of Samer’s photograph, a man stared in shock at the scene, with his hands resting on his head, while another carried body parts. Bystanders searched for survivors under rubble from the building. Another man picked up a piece of bread, lying next to someone’s slippers.

The reason for the attack was unclear, but activists said that rebel fighters occupied Hilfaya last week as part of a broader offensive to seize territory around the city of Hama, where the government has kept tight control after suppressing protests in the city last year.

Civilians have been caught between the two sides. On Friday, rebel fighters posted a video threatening to attack Christian villages with artillery while asserting that the residents were shielding government loyalists. In the last few days, Hilfaya had come under repeated shelling from loyalist positions in a neighboring village, activists said.

The bakery was one of three in the city. When word that a flour shipment from Turkey had come in spread on Sunday, Sunday, people began lining up around noon, waiting their turn at its windows for bread after a stretch of days when the bakeries had been idled. At least three bombs fell near the bakery, Samer and other activists said.

The attack came as the international envoy to Syria, Lakhdar Brahimi, arrived in the capital, Damascus, where he was expected to meet with President Bashar al-Assad. His visit was rumored but not previously announced, signaling concerns about security as the fighting between opposition fighters and the government intensifies in the capital.

Mr. Brahimi made no public comment on Sunday, and the Syrian information minister said during a news conference that he had no knowledge of the envoy’s visit. Mr. Brahimi traveled by land from Beirut because of ongoing fighting between opposition fighters and the government near Damascus Airport, Lebanese airport officials told The Associated Press.

His visit was also likely to add fuel to the growing speculation about a deal to remove Mr. Assad from power, as rebel forces have claimed gains near government strongholds and as international aid agencies warn of a growing humanitarian crisis in the winter months.

Russia, one of Syria’s most reliable allies, has recently given signals that it is distancing itself from the Syrian president. On Saturday, the Russian foreign minister, Sergey V. Lavrov, said several countries in the region had offered Mr. Assad asylum, while adding that Moscow was not willing to mediate on their behalf.

Ellen Barry contributed reporting from Moscow, Hala Droubi from Jidda, Saudi Arabia, and Hwaida Saad from Beirut.

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UK paper suing Lance Armstrong over libel case

LONDON (AP) — Lance Armstrong is being sued for more than $1.5 million by a British newspaper over the settlement of a libel action, which followed doping allegations against the cyclist that it published.

The Sunday Times paid Armstrong 300,000 pounds (now about $485,000) in 2006 to settle a case after it reprinted claims from a book in 2004 that he took performance-enhancing drugs.

The U.S. Anti-Doping Agency concluded this year that Armstrong led a massive doping program on his teams. Armstrong was stripped of his seven Tour de France titles and banned from cycling for life.

The Sunday Times announced in an article in its latest edition that it has issued legal papers against Armstrong.

"It is clear that the proceedings were baseless and fraudulent," the paper said in a letter to Armstrong's lawyers. "Your representations that you had never taken performance enhancing drugs were deliberately false."

The paper, which is owned by Rupert Murdoch's News Corp., said its total claim against Armstrong is "likely to exceed" 1 million pounds ($1.6 million).

"The Sunday Times is now demanding a return of the settlement payment plus interest, as well as its costs in defending the case," the paper said.

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Genetic Gamble : Drugs Aim to Make Several Types of Cancer Self-Destruct

C.J. Gunther for The New York Times

Dr. Donald Bergstrom is a cancer specialist at Sanofi, one of three companies working on a drug to restore a tendency of damaged cells to self-destruct.

For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.

Great uncertainties remain, but such drugs could mean new treatments for rare, neglected cancers, as well as common ones. Merck, Roche and Sanofi are racing to develop their own versions of a drug they hope will restore a mechanism that normally makes badly damaged cells self-destruct and could potentially be used against half of all cancers.

No pharmaceutical company has ever conducted a major clinical trial of a drug in patients who have many different kinds of cancer, researchers and federal regulators say. “This is a taste of the future in cancer drug development,” said Dr. Otis Webb Brawley, the chief medical and scientific officer of the American Cancer Society. “I expect the organ from which the cancer came from will be less important in the future and the molecular target more important,” he added.

And this has major implications for cancer philanthropy, experts say. Advocacy groups should shift from fund-raising for particular cancers to pushing for research aimed at many kinds of cancer at once, Dr. Brawley said. John Walter, the chief executive officer of the Leukemia and Lymphoma Society, concurred, saying that by pooling forces “our strength can be leveraged.”

At the heart of this search for new cancer drugs are patients like Joe Bellino, who was a post office clerk until his cancer made him too sick to work. Seven years ago, he went into the hospital for hernia surgery, only to learn he had liposarcoma, a rare cancer of fat cells. A large tumor was wrapped around a cord that connects the testicle to the abdomen. “I was shocked,” he said in an interview this summer.

Companies have long ignored liposarcoma, seeing no market for drugs to treat a cancer that strikes so few. But it is ideal for testing Sanofi’s drug because the tumors nearly always have the exact genetic problem the drug was meant to attack — a fusion of two large proteins. If the drug works, it should bring these raging cancers to a halt. Then Sanofi would test the drug on a broad range of cancers with a similar genetic alteration. But if the drug fails against liposarcoma, Sanofi will reluctantly admit defeat.

“For us, this is a go/no-go situation,” said Laurent Debussche, a Sanofi scientist who leads the company’s research on the drug.

The genetic alteration the drug targets has tantalized researchers for decades. Normal healthy cells have a mechanism that tells them to die if their DNA is too badly damaged to repair. Cancer cells have grotesquely damaged DNA, so ordinarily they would self-destruct. A protein known as p53 that Dr. Gary Gilliland of Merck calls the cell’s angel of death normally sets things in motion. But cancer cells disable p53, either directly, with a mutation, or indirectly, by attaching the p53 protein to another cellular protein that blocks it. The dream of cancer researchers has long been to reanimate p53 in cancer cells so they will die on their own.

The p53 story began in earnest about 20 years ago. Excitement ran so high that, in 1993, Science magazine anointed it Molecule of the Year and put it on the cover. An editorial held out the possibility of “a cure of a terrible killer in the not too distant future.”

Companies began chasing a drug to restore p53 in cells where it was disabled by mutations. But while scientists know how to block genes, they have not figured out how to add or restore them. Researchers tried gene therapy, adding good copies of the p53 gene to cancer cells. That did not work.

Then, instead of going after mutated p53 genes, they went after half of cancers that used the alternative route to disable p53, blocking it by attaching it to a protein known as MDM2. When the two proteins stick together, the p53 protein no longer functions. Maybe, researchers thought, they could find a molecule to wedge itself between the two proteins and pry them apart.

The problem was that both proteins are huge and cling tightly to each other. Drug molecules are typically tiny. How could they find one that could separate these two bruisers, like a referee at a boxing match?

In 1996, researchers at Roche noticed a small pocket between the behemoths where a tiny molecule might slip in and pry them apart. It took six years, but Roche found such a molecule and named it Nutlin because the lab was in Nutley, N.J.

But Nutlins did not work as drugs because they were not absorbed into the body.

Roche, Merck and Sanofi persevered, testing thousands of molecules.

At Sanofi, the stubborn scientist leading the way, Dr. Debussche, maintained an obsession with p53 for two decades. Finally, in 2009, his team, together with Shaomeng Wang at the University of Michigan and a biotech company, Ascenta Therapeutics, found a promising compound.

The company tested the drug by pumping it each day into the stomachs of mice with sarcoma.

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Genetic Gamble : Drugs Aim to Make Several Types of Cancer Self-Destruct

C.J. Gunther for The New York Times

Dr. Donald Bergstrom is a cancer specialist at Sanofi, one of three companies working on a drug to restore a tendency of damaged cells to self-destruct.

For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.

Great uncertainties remain, but such drugs could mean new treatments for rare, neglected cancers, as well as common ones. Merck, Roche and Sanofi are racing to develop their own versions of a drug they hope will restore a mechanism that normally makes badly damaged cells self-destruct and could potentially be used against half of all cancers.

No pharmaceutical company has ever conducted a major clinical trial of a drug in patients who have many different kinds of cancer, researchers and federal regulators say. “This is a taste of the future in cancer drug development,” said Dr. Otis Webb Brawley, the chief medical and scientific officer of the American Cancer Society. “I expect the organ from which the cancer came from will be less important in the future and the molecular target more important,” he added.

And this has major implications for cancer philanthropy, experts say. Advocacy groups should shift from fund-raising for particular cancers to pushing for research aimed at many kinds of cancer at once, Dr. Brawley said. John Walter, the chief executive officer of the Leukemia and Lymphoma Society, concurred, saying that by pooling forces “our strength can be leveraged.”

At the heart of this search for new cancer drugs are patients like Joe Bellino, who was a post office clerk until his cancer made him too sick to work. Seven years ago, he went into the hospital for hernia surgery, only to learn he had liposarcoma, a rare cancer of fat cells. A large tumor was wrapped around a cord that connects the testicle to the abdomen. “I was shocked,” he said in an interview this summer.

Companies have long ignored liposarcoma, seeing no market for drugs to treat a cancer that strikes so few. But it is ideal for testing Sanofi’s drug because the tumors nearly always have the exact genetic problem the drug was meant to attack — a fusion of two large proteins. If the drug works, it should bring these raging cancers to a halt. Then Sanofi would test the drug on a broad range of cancers with a similar genetic alteration. But if the drug fails against liposarcoma, Sanofi will reluctantly admit defeat.

“For us, this is a go/no-go situation,” said Laurent Debussche, a Sanofi scientist who leads the company’s research on the drug.

The genetic alteration the drug targets has tantalized researchers for decades. Normal healthy cells have a mechanism that tells them to die if their DNA is too badly damaged to repair. Cancer cells have grotesquely damaged DNA, so ordinarily they would self-destruct. A protein known as p53 that Dr. Gary Gilliland of Merck calls the cell’s angel of death normally sets things in motion. But cancer cells disable p53, either directly, with a mutation, or indirectly, by attaching the p53 protein to another cellular protein that blocks it. The dream of cancer researchers has long been to reanimate p53 in cancer cells so they will die on their own.

The p53 story began in earnest about 20 years ago. Excitement ran so high that, in 1993, Science magazine anointed it Molecule of the Year and put it on the cover. An editorial held out the possibility of “a cure of a terrible killer in the not too distant future.”

Companies began chasing a drug to restore p53 in cells where it was disabled by mutations. But while scientists know how to block genes, they have not figured out how to add or restore them. Researchers tried gene therapy, adding good copies of the p53 gene to cancer cells. That did not work.

Then, instead of going after mutated p53 genes, they went after half of cancers that used the alternative route to disable p53, blocking it by attaching it to a protein known as MDM2. When the two proteins stick together, the p53 protein no longer functions. Maybe, researchers thought, they could find a molecule to wedge itself between the two proteins and pry them apart.

The problem was that both proteins are huge and cling tightly to each other. Drug molecules are typically tiny. How could they find one that could separate these two bruisers, like a referee at a boxing match?

In 1996, researchers at Roche noticed a small pocket between the behemoths where a tiny molecule might slip in and pry them apart. It took six years, but Roche found such a molecule and named it Nutlin because the lab was in Nutley, N.J.

But Nutlins did not work as drugs because they were not absorbed into the body.

Roche, Merck and Sanofi persevered, testing thousands of molecules.

At Sanofi, the stubborn scientist leading the way, Dr. Debussche, maintained an obsession with p53 for two decades. Finally, in 2009, his team, together with Shaomeng Wang at the University of Michigan and a biotech company, Ascenta Therapeutics, found a promising compound.

The company tested the drug by pumping it each day into the stomachs of mice with sarcoma.

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