James leads Heat over Thunder in Finals rematch

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MIAMI (AP) — Kevin Durant and Russell Westbrook combined to score 54 points, more than any set of teammates had managed in a game against Miami all season.


Oklahoma City needed them to score at least three more.


That didn't happen, and an NBA Finals rematch went just as last year's title series did — to the Heat.


LeBron James had 29 points, nine assists and eight rebounds, Dwyane Wade scored 21, and the Heat survived a frantic finish to beat the Thunder 103-97 on Tuesday night, a game where Durant and Westbrook both missed potential tying 3-pointers in the final seconds.


"A great game to play," Thunder coach Scott Brooks said, "and a great game to coach."


For the Heat, it was just a little greater.


Mario Chalmers scored a season-high 20 for the Heat, who were 19 for 19 from the foul line, the second-best effort in franchise history behind only a 30-for-30 game in Boston on March 24, 1993. Chris Bosh added 16 points for Miami, which has beaten the Thunder five straight times dating to last June's title series.


"Felt a little bit like a different month," Heat coach Erik Spoelstra said. "Regardless of what your script is coming into the game, when you play this team, it's not going to go according to script. They're too good."


It's the first losing streak of the season for the Thunder, who had been 4-0 after losses. Serge Ibaka and Kevin Martin each scored 15 for Oklahoma City.


The game had a little of everything — a fast start by the reigning champions, a one-handed dunk by James on an offensive rebound that will be added to his copious highlight reel, a scrum after a hard foul that led to double-technicals on Wade and Ibaka early in the fourth, an easy rally by the Thunder from an early double-digit deficit, and even workout partners in Durant and James barking back and forth in the final minutes.


Such was the intensity that James slumped over the scorer's table with 1:08 left, exhausted.


"I'm tired as hell right now," James said — and that was more than an hour after the game ended.


With good reason. On an emotional day, there was a wild finish.


Wade lost the ball on an ill-advised, behind-the-back dribble, and the turnover set up Durant for a two-handed dunk that got the Thunder within 96-95 with 44.1 seconds remaining.


Needing a stop on the next trip, the Thunder instead forgot to play defense. Kendrick Perkins and Ibaka both were confused on the ensuing Miami possession, and Bosh was left alone to take a pass from James and throw down a dunk that restored Miami's three-point edge.


"We went over and helped," Durant said. "We just needed to help on the backside. There was miscommunication but we still had a chance to go into overtime."


Two chances, actually.


Oklahoma City got within one when Durant made a jumper over James, but no closer. Ray Allen's two free throws with 15.6 seconds left made it 100-97, and Miami's last three points came from the line. Durant missed a 3-pointer that James contested, Westbrook wound up with a second chance that Wade defended, and the Thunder guard smacked a nearby table arguing that he was fouled.


"Part of the game," Westbrook said.


While the stars were stars, the Heat got help from one unexpected source. Chalmers was making everything, even unintended plays. Allen lost possession on what looked to be a pass to no one, but Chalmers picked up the bouncing ball on the right wing, whirled and made a 3-pointer — putting Miami up 86-79 with 8:14 left.


In the end, that cushion was necessary.


"I got going early," Chalmers said, "and I stuck with it."


The Heat came out flying, opening a quick 13-2 lead after making six of their first seven shots. About all that didn't go right for the Heat early on was James committing a foul, the first time he was called for a personal since Dec. 8.


It happened 4:03 into the game — 254 minutes and 7 seconds of on-court time since his last one — when James fouled Ibaka on a dunk attempt.


Chalmers had 12 points, matching his season high, in the opening quarter alone, and that was also Miami's lead after his layup for a 15-3 edge. When Durant headed to the bench after being called for his second personal, plus a technical, with 2:08 left in the first, the Heat led 27-16.


But even with Durant out, Oklahoma City scored the last eight points of the quarter, six coming from the line. The Thunder shot 17 of the game's first 18 free throws and finished with a 38-19 edge in tries from the stripe.


The Heat were held to two points in the first 5:05 of the third, and the Thunder grabbed the lead for the first time. Durant connected on a baseline jumper while falling out of bounds and getting fouled by James. The resulting free throw gave Oklahoma City a 58-56 edge.


With that, the back-and-forth began, and Miami found a way.


"Both teams really played up to the billing," Wade said. "An excellent basketball game."


NOTES: James scored at least 20 points for the 30th straight regular-season game and 46th overall. ... Wade is 7-1 on Christmas, and James has won six straight on the holiday. ... Miami's Mike Miller became the 48th active player to reach 10,000 points. ... The Thunder have used the same starting lineup for all 27 games. ... James passed Bernard King for 39th on the NBA career scoring list. ... Attendance was 20,300, the largest crowd for a Heat home game since they moved into AmericanAirlines Arena.


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No Easy Route If Assad Opts to Go, or Stay

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BEIRUT, Lebanon — President Bashar al-Assad of Syria sits in his mountaintop palace as the tide of war licks at the cliffs below.




Explosions bloom over the Damascus suburbs. His country is plunging deeper into chaos. The United Nations’ top envoy for the Syrian crisis, Lakhdar Brahimi, met with Mr. Assad in the palace on Monday in an urgent effort to resolve the nearly two-year-old conflict.


How Mr. Assad might respond to Mr. Brahimi’s entreaty depends on his psychology, shaped by a strong sense of mission inherited from his iron-fisted father and predecessor, Hafez al-Assad; his closest advisers, whom supporters describe as a hard-line politburo of his father’s gray-haired security men; and Mr. Assad’s assessment, known only to himself, about what awaits him if he stays — victory, or death at the hands of his people.


From his hilltop, Mr. Assad can gaze toward several possible futures.


East of the palace lies the airport and a possible dash to exile, a route that some say Mr. Assad’s mother and wife may have already taken. But the way is blocked, not just by bands of rebels, but by a belief that supporters say Mr. Assad shares with his advisers that fleeing would betray both his country and his father’s legacy.


He can stay in Damascus and cling to — even die for — his father’s aspirations, to impose a secular Syrian order and act as a pan-Arab leader on a regional and global stage.


Or he can head north to the coastal mountain heartland of his minority Alawite sect, ceding the rest of the country to the uprising led by the Sunni Muslim majority. That would mean a dramatic comedown: reverting to the smaller stature of his grandfather, a tribal leader of a marginalized minority concerned mainly with its own survival.


Mr. Brahimi was closemouthed about the details of his meeting, but has warned in recent weeks that without a political solution, Syria faces the collapse of the state and years of civil war that could dwarf the destruction already caused by the conflict that has taken more than 40,000 lives.


A Damascus-based diplomat said Monday that Mr. Assad, despite official denials, was “totally aware” that he must leave and was “looking for a way out,” though the timetable is unclear.


“More importantly,” said the diplomat, who is currently outside Syria but whose responsibilities include the country, “powerful people in the upper circle of the ruling elite in Damascus are feeling that an exit must be found.”


Yet others close to Mr. Assad and his circle say any retreat would clash with his deep-seated sense of himself, and with the wishes of increasingly empowered security officials, whom one friend of the president’s has come to see as “hotheads.”


Mr. Assad believes he is “defending his country, his people, and his regime and himself” against Islamic extremism and Western interference, said Joseph Abu Fadel, a Lebanese political analyst who supports Mr. Assad and met with government officials last week in Damascus.


Analysts in Russia, one of Syria’s staunchest allies, say that as rebels try to encircle Damascus and cut off escape routes to the coast, the mood in the palace is one of panic, evinced by the erratic use of weapons: Scud missiles better used against an army than an insurgency, naval mines dropped from the air instead of laid at sea.


But even if Mr. Assad wanted to flee, it is unclear if the top generals would let him out alive, Russian analysts say, since they believe that if they lay down arms they — and their disproportionately Alawite families — will die in vengeance killings, and need him to rally troops.


“If he can fly out of Damascus,” Semyon A. Bagdasarov, a Middle East expert in Moscow, said — at this, he laughed dryly — “there is also the understanding of responsibility before the people. A person who has betrayed several million of those closest to him.”


Many Syrians still share Mr. Assad’s belief that he is protecting the Syrian state, which helps explain how he has held on this long. At a lavish lunch hosted by a Lebanese politician outside Beirut in September, prominent Syrian backers of Mr. Assad — Alawites, Sunnis and Christians — spoke of the president, over copious glasses of Johnnie Walker scotch, as the bulwark of a multicultural, modern Syria.


Reporting was contributed by Kareem Fahim and David D. Kirkpatrick from Beirut, Ellen Barry from Moscow, Sebnem Arsu from Istanbul, Rick Gladstone from New York, and an employee of The New York Times from Tartus, Syria.



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Pagano back to coach Colts after cancer treatment

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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."


___


Online: http://pro32.ap.org/poll and http://twitter.com/AP_NFL


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Despite Billions in Aid, Reconstruction in Haiti Stalls

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Colts recovering coach returns to team facility

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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.


___


Online: http://pro32.ap.org/poll and http://twitter.com/AP_NFL


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N.Y.U. and Others Offer Shorter Courses Through Medical School

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Training to become a doctor takes so long that just the time invested has become, to many, emblematic of the gravity and prestige of the profession.




But now one of the nation’s premier medical schools, New York University, and a few others around the United States are challenging that equation by offering a small percentage of students the chance to finish early, in three years instead of the traditional four.


Administrators at N.Y.U. say they can make the change without compromising quality, by eliminating redundancies in their science curriculum, getting students into clinical training more quickly and adding some extra class time in the summer.


Not only, they say, will those doctors be able to hang out their shingles to practice earlier, but they will save a quarter of the cost of medical school — $49,560 a year in tuition and fees at N.Y.U., and even more when room, board, books, supplies and other expenses are added in.


“We’re confident that our three-year students are going to get the same depth and core knowledge, that we’re not going to turn it into a trade school,” said Dr. Steven Abramson, vice dean for education, faculty and academic affairs at N.Y.U. School of Medicine.


At this point, the effort involves a small number of students at three medical schools: about 16 incoming students at N.Y.U., or about 10 percent of next year’s entering class; 9 at Texas Tech Health Science Center School of Medicine; and even fewer, for now, at Mercer University School of Medicine’s campus in Savannah, Ga. A similar trial at Louisiana State University has been delayed because of budget constraints.


But Dr. Steven Berk, the dean at Texas Tech, said that 10 or 15 other schools across the country had expressed interest in what his university was doing, and the deans of all three schools say that if the approach works, they will extend the option to larger numbers of students.


“You’re going to see this kind of three-year pathway become very prominent across the country,” Dr. Abramson predicted.


The deans say that getting students out the door more quickly will accomplish several goals. By speeding up production of physicians, they say, it could eventually dampen a looming doctor shortage, although the number of doctors would not increase unless the schools enrolled more students in the future.


The three-year program would also curtail student debt, which now averages $150,000 by graduation, and by doing so, persuade more students to go into shortage areas like pediatrics and internal medicine, rather than more lucrative specialties like dermatology.


The idea was supported by Dr. Ezekiel J. Emanuel, a former health adviser to President Obama, and a colleague, Victor R. Fuchs. In an editorial in the Journal of the American Medical Association in March, they said there was “substantial waste” in the nation’s medical education. “Years of training have been added without evidence that they enhance clinical skills or the quality of care,” they wrote. They suggested that the 14 years of college, medical school, residency and fellowship that it now takes to train a subspecialty physician could be reduced by 30 percent, to 10 years.


That opinion, however, is not universally held. Other experts say that a three-year medical program would deprive students of the time they need to delve deeply into their subjects, to consolidate their learning and to reach the level of maturity they need to begin practicing, while adding even more pressure to a stressful academic environment.


“The downside is that you are really tired,” said Dr. Dan Hunt, co-secretary of the Liaison Committee on Medical Education, the accrediting agency for medical schools in the United States and Canada. But because accreditation standards do not dictate the fine points of curriculum, the committee has approved N.Y.U.’s proposal, which exceeds by five weeks its requirement that schools provide at least 130 weeks of medical education.


The medical school is going ahead with its three-year program despite the damage from Hurricane Sandy, which forced NYU Langone Medical Center to evacuate more than 300 patients at the height of the storm and temporarily shut down three of its four main teaching hospitals.


Dr. Abramson of N.Y.U. said that postgraduate training, which typically includes three years in a hospital residency, and often fellowships after that, made it unnecessary to try to cram everything into the medical school years. Students in the three-year program will have to take eight weeks of class before entering medical school, and stay in the top half of their class academically. Those who do not meet the standards will revert to the four-year program.


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IHT Rendezvous: Adding More Bricks to the Great Firewall of China

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HONG KONG — China appears to have reinforced its Internet firewall in recent days, blocking some of the leading services that allow people on the mainland to access forbidden sites like Twitter, Facebook and YouTube.

International business transactions also are being affected, Internet analysts said. The New York Times Web site remains 100 percent blocked on the mainland, along with the Chinese-language edition of The Times and Rendezvous.

At least three foreign companies — Astrill, WiTopia and StrongVPN — have apologized to customers whose virtual private networks, or VPNs, have been slowed or disabled. VPNs are used to circumvent the Communist government’s firewall. The companies, meanwhile, were suggesting some work-arounds.

The daily newspaper Global Times, affiliated with the Communist Party, acknowledged the firewall had been “upgraded,” but it also warned that foreign providers of VPN services were operating illegally.

China blocks online searches of politically sensitive terms, smothers embarrassing news events, blocks online messages from dissidents and simply deletes any microblog posts that it dislikes.

The firewall also blocks countless Web sites that are openly available to users elsewhere around the world — from pornography sites and commercial come-ons to news reporting, political activism and religious proselytizing. Users on the mainland thus have to use VPNs to reach the banned sites.

Liu Xiao Ming, the Chinese ambassador to Britain, told the BBC on Friday that there was “a misconception about the Internet and development in China.”

“In fact, the Chinese are very much open in terms of the Internet,” he said, quoted in an article in The South China Morning Post. “In fact, we have the most number of Internet users in China today.”

An estimated 600 million Chinese have access to the Internet.

Foreign businesses also use VPNs not only to safeguard their transactions but also to keep government censors and rival companies from seeing their corporate communications.

Global Times quoted an anonymous executive at a foreign technology company operating in China who said the lack of a VPN would damage the firm’s operations.

Josh Ong, China editor of the tech monitoring site The Next Web, said in an interview with the Voice of America that international companies were reporting disruptions in their corporate VPN services.

“A lot of companies have a general policy that they must use their own proxy network in order to transfer data, especially into and out of China,” Mr. Ong said. “So you are looking at banks or e-commerce companies, anyone who is transferring very sensitive information, a lot of them use corporate VPNs.”

Mr. Ong suggested that the tightening of the firewall could be tied to the recent leadership change in the Chinese Communist Party.

“It is certainly possible that some of it is just a general flexing of might, kind of coming in with a strong arm to really show who’s in control,” he said. “But there is definitely something intentional happening when these VPN services are being restricted.”

As Bill Bishop wrote recently on DealBook, China’s management of the Internet “has not been encouraging for those who want to believe the leadership will push reforms.”

“I have lived in Beijing since 2005, and these have been the most draconian few days of Internet restrictions I have experienced,” he said last month.

“Indiscriminate blocking of major parts of the global Internet is not going to help China in its quest to internationalize the renminbi and make it a reserve currency,” Bill said. “Internet controls at the level of the last few days may also deter foreign firms from moving their regional headquarters to China.”

Barbara Demick of The Los Angeles Times bureau in Beijing offered this cautionary tweet:

My colleagues Sharon LaFraniere and David Barboza wrote about similar concerns over China’s Internet censorship last year, and they spoke to Duncan Clark, chairman of BDA China, an investment and strategy consultancy based in Beijing.

“It has been double the guard, and double the guard, and you never hear proclamations about things being relaxed,” said Mr. Clark, a 17-year resident of China. “We have never seen this level of control in the time I have been here, and I have been here since the beginning of the Internet.”

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UK paper suing Lance Armstrong over libel case

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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

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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

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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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