By RON WINSLOW

By reducing the activity of one type of gene, scientists said they increased the average life span of mice by about 20%, a feat that in human terms is akin to extending life by about 15 years.

Moreover, the researchers at the National Institutes of Health found that memory, cognition and some other important traits were better preserved in the mice as they aged, compared with a control group of mice that had normal levels of a protein put out by the gene.

The findings, published Thursday in the journal Cell Reports, strengthen the case that the gene, called mTOR, is a major regulator of the aging process.

The mice were bred to put out just 25% of the normal levels of mTOR protein, indicating that suppressing the activity of the gene “clearly makes mice live longer,” said Toren Finkel, head of the laboratory of molecular biology in NIH’s National Heart, Lung and Blood Institute and senior author of the new study.

Though mouse studies don’t always translate to humans, Dr. Finkel and other researchers said the results raise the possibility that targeting the gene with drugs that inhibit its activity might one day be at least part of a strategy for prolonging longevity in people.

Such a drug, an immunosuppressant called rapamycin, and some similar agents already are on the market and used to treat certain diseases, but researchers cautioned against taking such medicines, which have side effects, for anything but approved uses.

The results also build on a growing body of research challenging the belief that aging is an intractable biological process, prompting scientists to think of slowing aging as a possible way to prevent disease.

“What we need right now is for scientists and the public to wake up to the concept that you can slow aging,” said Brian Kennedy, president of the Buck Institute for Aging Research in Novato, Calif., who wasn’t involved in the new study. “If you do, you prevent many of the diseases that we’re so scared of and that are associated with aging.” They include cardiovascular disease, cancer and Alzheimer’s disease.

Major hurdles stand in the path of translating the findings to humans, including whether inhibiting the action of mTOR would have similar life-extending effects, and if it did whether the benefit would come without unwanted problems.

The mice in the study had softer bones, developed more infections—probably from a depressed immune system—and may have had a higher risk of cataracts than normal mice, the researchers found. But they were also significantly less likely to develop cancer, Dr. Finkel said.

The mTOR gene has a well-established role in the metabolism and energy balance of cells, and researchers believe it is associated with the concept of caloric restriction. It has been known for about a century that animals that eat less live longer.

When there are a lot of calories present in cells, mTOR activity is turned up, “signaling the cell to grow and divide,” Dr. Kennedy said. “If there are fewer calories, the pathway is turned down and that signals the cell to stop proliferating and become stress resistant.” That helps animals live longer, he said.

The name mTOR stands for mechanistic target of rapamycin, a drug used in certain treatments for cancer and heart disease and also to suppress the immune system to prevent rejection of organ transplants.

“It’s early days to suggest that rapamycin is something that people would want to take” to increase longevity,” said David Sabatini, professor of biology at the Massachusetts Institute of Technology and the Whitehead Institute for Biomedical Research in Cambridge, Mass., who wasn’t involved in Thursday’s study. “But [research] is clearly hinting at a pathway that matters.”

In the study, Dr. Finkel found that the median life span for the mTOR-deficient mice was 28 months for males and 31.5 months for females, compared with the span for normal mice of 22.9 months for males and 26.5 months for females.

 

By
• RON WINSLOW

Kellie Carey’s doctor finally stopped dodging questions about how long she had to live six weeks after he diagnosed her lung cancer.

“Maybe three months,” he told her in his office one sunny May morning in 2010, she recalls.

Yet she is still alive, a testament to the most extraordinary decade of progress ever in the long scientific struggle against lung cancer.

Tests found Ms. Carey’s lung cancer to be of a rare type that researchers had found just three years earlier by deciphering its genetic code. The 45-year-old businesswoman in 2010 went on a drug Pfizer Inc. PFE +0.27% was testing for that type. By pinpointing her cancer, the drug probably helped give her years more to live than chemotherapy would have, her doctors say.

That is remarkable because lung cancer for decades defied efforts to find drugs that could extend an average patient’s life by even a few weeks.

But an explosion in knowledge about the genetic mutations that cause tumors is just now offering the first real promise of drugs that can control what is the most-common and most-deadly cancer.

Ms. Carey has one of at least 15 lung-cancer variations, almost all of which scientists didn’t know existed 10 years ago. Researchers have identified those variations, most of them in just the past four years, by decoding DNA in tumors—akin to how crime labs analyze DNA to genetically fingerprint suspects.

The drugs don’t cure cancer and face significant hurdles. But doctors now talk of a “precision medicine” approach in which those pinpoint drugs can treat tumors far more effectively than catchall chemotherapy.

“What we’re seeing is the beginning of a revolution in therapeutics,” says Janet Woodcock, director of the Food and Drug Administration’s Center for Drug Evaluation and Research. “We can only hope that this gets us to where cancer is managed or curable.”

Among signs that revolution really is afoot: A June 2013 study found that lung-cancer patients who were treated with drugs targeted at their genetically identified varieties lived 1.4 years longer than patients on chemotherapy whose cancers weren’t genetically identified.

In effect, lung cancer is no longer a few common diagnoses. Instead, it is a growing list of rare cancers, each a target for its own drug regimen.

“It’s likely that more than half of tumors have some alteration we can target with a drug,” says John V. Heymach, a lung-cancer specialist at MD Anderson Cancer Center, Houston. “They may not all have the same success, but we know that in many cases, a targeted agent will work very well.”

The same goes for other malignancies: Scientists have decoded tumor DNA from breast, colon, kidney, skin and other cancers in recent years to discover scores of variations they didn’t know existed before.

Research hospitals like MD Anderson, Vanderbilt University and Massachusetts General Hospital are among a growing number of cancer practices that routinely decode the tumor DNA of most patients with advanced cancer.

The lists of newfound variations have invigorated the drug industry, with companies like Pfizer, Roche Holding AG ROG.VX +0.38% andMerck MRK -0.08% & Co. racing to develop drugs that target each one.

Last year, nearly 1,000 cancer drugs were in clinical development, up 52% from 2006, says the Pharmaceutical Research and Manufacturers of America, a trade group. The “vast majority” of that growth is from drugs targeted at genetic mutations, says Bill Chin, the group’s head of science and regulatory affairs.

Three drugs are on the market for newly discovered lung-cancer mutations. Dozens more are in clinical trials. Some approved for other cancers appear effective for specific lung cancers. And drug companies are targeting other mutations of all cancer types.

At least half the 27 medicines on Novartis AG’s NOVN.VX +0.74%current list of oncology drugs in clinical development target cancer mutations. Precision medicine is “fundamentally changing the way we think about cancer drug development,” says Hervé Hoppenot, president of the company’s Novartis Oncology unit.

Just last year, the FDA established a “breakthrough therapy designation” to hasten approval of experimental drugs that show striking benefits in early trials, including those targeted at cancer mutations.

Ms. Carey’s diagnosis in 2010 came just as that thinking was starting to change. Her roller-coaster ride of cancer remission and recurrence over the next three years shows the promise and shortcomings of precision medicine.

Ms. Carey, who worked for a business selling private jets, suffered an apparent seizure at her gym. Doctors discovered a nodule in her lung of cancer that had spread to her brain. Surgery and radiation treated the brain tumor.

But when the New York City resident’s doctor said she probably had three months left, “I definitely felt like there were no options,” she says.

It wasn’t an unusual prognosis for lung cancer in 2010. Three decades of research starting in the 1970s into hundreds of potential lung-cancer drugs had produced dismal results, says MD Anderson’s Dr. Heymach: Over that time, a lung-cancer patient’s median survival improved by just one month, to eight months.

Ms. Carey found hope in news accounts of a drug Pfizer was testing against a cancer type researchers had identified in 2007. The type was caused by a mutation in the so-called ALK gene—it normally plays a role in brain development—and Ms. Carey wanted to know if that was her cancer.

In 2010, precision medicine was still so nascent that Ms. Carey had to show unusual persistence. Few doctors even considered testing tumors for mutations.

She says she had to demand the test. “Are you helping to save my life,” she recalls asking her doctor at the time, “or just waiting for me to die?”

That ALK-gene mutation was only the second mutation researchers had identified using advanced DNA-sequencing technology on lung-cancer tumors. The first was in 2004, a mutation in the so-called EGFR gene that responded well to an existing drug, Tarceva, now sold by Roche. (Another mutation, KRAS was discovered previously, with earlier technology.)

The discovery of the role of the EGFR mutation in 2004 sparked the search for more cancer-causing mutations.

Before that, a pathologist would identify a patient’s lung-cancer tumors through a microscope to see if they were of the “small-cell” or “non-small-cell” variety. The difference helped determine which regimen of chemotherapy to prescribe.

After finding the ALK-gene mutation, researchers in 2007 found another mutation. By 2010, for a few lucky patients whose tumors proved to be of the newly discovered varieties, there were a few drugs on the market or in trials.

Ms. Carey was among the fortunate: Her mutation proved to be of the ALK gene, which represents about 5% of lung-cancer cases.

The discovery of the ALK-gene mutation had prompted Pfizer to test a drug already in its portfolio, brand-named Xalkori and generically called crizotinib, to see if it worked on the mutation. Pfizer’s study of the first patients showed dramatic results, which Ms. Carey read about.

Again, Ms. Carey needed persistence, this time to get the drug. She visited different sites participating in Pfizer’s trials before finding a slot at the University of Chicago.

Within six weeks, two of three cancerous nodules in her lungs had disappeared, and the third had shrunk significantly.

The FDA approved the Pfizer drug in 2011 based on 250 patients, four years after the ALK-mutation link was discovered. That is lightning speed in an industry accustomed to spending a decade with thousands of test subjects to get drug approval.

Ms. Carey in 2011 began buying the Pfizer drug by prescription. It was expensive—today Pfizer charges $10,800 a month for it—but her insurance covered it.

Prices like that raise questions about the affordability of precision medicine. But those prices, and the speed at which genetically targeted drugs can come to market, had begun changing the economics of drug development.

The “precision medicine approach requires people to change the way they look at opportunities,” says Mace Rothenberg, a senior vice president who heads cancer clinical development for Pfizer. Instead of trying to apply a drug to the largest number of patients possible, it is possible to “demonstrate very significant value of the drug to the patient, the physician, the payers and the company.”

Discovery of new mutations accelerated. A 2011 report linked a mutation of a gene called RET to lung cancer, prompting researchers at Memorial Sloan-Kettering Cancer in New York to approach ExelixisInc. EXEL -0.61% The South San Francisco biotechnology company was developing a drug called cabozantinib to treat a rare form of thyroid cancer linked to the RET mutation.

That mutation is found in only about 1% of lung-cancer patients, but Sloan-Kettering launched a drug trial. The first few patients tested had striking benefits. “These were patients who had nothing six months earlier,” says Mark Kris, a lung-cancer specialist at Sloan-Kettering.

Discovery of still-more lung cancer mutations continued in rapid fire. The count is 15 today, accounting for about 60% of all lung cancers, according to some estimates, and researchers expect to find more.

Precision medicine is no cure. A tumor with a pinpointed mutation doesn’t always respond to a drug targeted at it. The drug often shrinks tumors within weeks. But the tumors can develop resistance and come roaring back.

Ms. Carey’s cancer found a way around the treatment, in early 2012. An analysis of her tumor found the ALK-gene mutation still active. She took to calling her mutation the “Darth Vader of cells.”

Doctors think most patients will need a series of precision drugs, sometimes with chemotherapy. “The tumor will keep evading our best therapies,” says Trever Bivona, a lung-cancer researcher at University of California San Francisco. “Ultimately we’re going to have to get to combination approaches.” exdiscovery of new

Ms. Carey in the spring of 2012 went off crizotinib for another regimen of brain radiation, then went back on the drug.

By that year, interest was surging among drug companies in targeted drugs. At least three “next-generation crizotinibs” against the ALK-gene mutation were now in trials. Ms. Carey entered a trial for one of them, being developed by Ariad Pharmaceuticals Inc. ARIA +0.27%

Not all patients can find a trial. Precision drugs are approved for only two lung-cancer mutations, the ALK and the EGFR-gene mutations. A patient with a different mutation must look for a drug in development and try to join its trial.

Dr. Bivona of University of California San Francisco says he treated a patient this year who died a month before the launch of a clinical trial for a drug that matched the patient’s mutation. “We were in a black hole,” he says. “Getting drugs to the patients who need them will take an entire remodeling of the drug-development system.”

While there are drugs approved for other cancers that appear effective for some newfound lung cancers, insurers generally feel data don’t yet justify coverage of such “off-label” drugs. And for several of the 15 known lung-cancer variants, an especially promising drug has yet to emerge.

Tests for mutations are less likely to be available in smaller doctors’ offices. Even many large centers are just putting in place systems to act on the information. “A lot of places can tell you they do this now, but few really have the people in place who know what to do,” says Roy Herbst, chief of medical oncology at Yale Cancer Center, New Haven, Conn., who is Ms. Carey’s current oncologist.

But rapid diagnostic advances are making it easier for any doctor to test for the newfound cancers. Tests now can hunt for more than 200 mutations—of lung and other cancers—in one biopsy.

Evidence that precision medicine works will likely broaden its use quickly. A June 2013 report on 1,007 patients with advanced lung cancer whose tumors were sequenced by a group of researchers called the Lung Cancer Mutation Consortium found that 62% had alterations suspected of being driver mutations.

The researchers reported that the 265 patients on the study treated with a targeted drug had a median survival of 3.5 years from diagnosis, compared with 2.1 years for the 361 patients for whom a mutation wasn’t identified.

“It opens up so many more doors for patients if you can find their target,” says Alice Shaw, an oncologist at Mass General in Boston.

At Ms. Carey’s checkup late this July, her doctor said her new drug regimen is keeping her lung tumor from progressing.

She is also considering a new class of drugs called PD-1 inhibitors that enlist the immune system. Such agents from Merck, Roche andBristol-Myers Squibb Co. BMY +0.51% are creating a buzz among oncologists for use in parallel with the genomic strategy.

“Now when I look back, I’m astonished at the timing of everything,” she says.

“My quality of life is extraordinary,” she says. “The science in this and the positive response I’ve had—I wouldn’t be alive without that.”

By

• SUMATHI REDDY
  

Going to bed at the same time every night could give your child’s brain a boost, a recent study found.

Researchers at University College London found that when 3-year-olds have a regular bedtime they perform better on cognitive tests administered at age 7 than children whose bedtimes weren’t consistent. The findings represent a new twist on an expanding body of research showing that inadequate sleep in children and adolescents hurts academic performance and overall health.

The latest study considered other factors that can influence bedtime and cognitive development, such as kids skipping breakfast or having a television in their bedroom. After accounting for these, the study found that going to bed very early or very late didn’t affect cognitive performance, so long as the bedtime was consistent.

“The surprising thing was the later bedtimes weren’t significantly affecting children’s test scores once we took other factors into account,” said Amanda Sacker, director of the International Center for Lifecourse Studies in Society and Health at University College London and a co-author of the study. “I think the message for parents is…maybe a regular bedtime even slightly later is advisable.”

The researchers suggested that having inconsistent bedtimes may hurt a child’s cognitive development by disrupting circadian rhythms. It also might result in sleep deprivation and therefore affect brain plasticity—changes in the synapses and neural pathways—at critical ages of brain development.

Sleep experts often focus largely on how much sleep children get. While that is important, “we tend to not pay as much attention to this issue of circadian disruption,” said Judith Owens, director of sleep medicine at Children’s National Medical Center in Washington, D.C., who wasn’t involved with the study.

Insufficient sleep and irregular bedtimes may each affect cognitive development through different mechanisms, Dr. Owens said. “The kid who has both [problems] may beat even higher risk for these cognitive impairments,” she said.

The study, published online in July in the Journal of Epidemiology & Community Health, examined data on bedtimes and cognitive scores for 11,178 children.

The children were participants in the U.K.’s Millennium Cohort Study, a nationally representative longterm study of infants born between 2000 and 2002.

Mothers were asked about their children’s bedtimes at 3, 5 and 7 years of age. Nearly 20% of the 3-year-olds didn’t have a regular bedtime. That figure dropped to 9.1% at age 5 and 8.2% at age 7. Mothers were also asked about socioeconomic and demographic characteristics and family routines.

When the children were 7 years old, they received cognitive assessments in reading, math and spatial abilities. The poorest test scores were recorded by children who went to bed very early or very late, and by those who had inconsistent bedtimes, said Dr. Sacker. But once other factors in the home were taken into account only the inconsistent bedtime was associated with lower scores, she said.

A consistent pattern of sleep behavior mattered. “Those who had irregular bedtimes at all three ages had significantly poorer scores than those who had regular bedtimes,” Dr. Sacker said. This was especially true for girls who didn’t establish consistent bedtimes between 3 and 7 years old.

Yvonne Kelly, a co-author of the study and a professor in the department of epidemiology and public health at University College London, said the researchers aren’t sure why girls seemed to be more affected. She noted that the difference in scores between these groups of girls and boys wasn’t statistically significant for the reading and spatial tests, but it was for the math test.

“I don’t think for one moment that boys are immune to these things and girls are more affected,” Dr. Kelly said.

The researchers didn’t have data on the total number of hours children slept overnight because mothers weren’t asked about what time the children woke up.

In general school-age kids—kindergarten through eighth-grade—should be getting about 10 hours of sleep, while 3- and 4-year-olds might need 11 to 13 hours, including day-time naps, said Shalini Paruthi, director of the pediatric sleep and research center at SSM Cardinal Glennon Children’s Medical Center at Saint Louis University.

Dr. Paruthi said the good news from the study is that the majority of the children went to bed at a consistent time, reinforcing advice from sleep specialists. “The younger the child is, the better it is to get into the habit of a regular bedtime,” said Dr. Paruthi, who wasn’t affiliated with the study. She recommends a 15-minute, pre-bedtime routine to help the brain transition from a more alert to a quiet state.

And in order to keep the body’s internal clock in sync with the brain, bedtimes on weekends and in the summer should only stray from the normal time by an hour or less, Dr. Paruthi said. “The internal clock in the brain and the body like to have consistency every day,” she said.

 

By

LAURA LANDRO

More than 50 years ago, scientists working in the City of Brotherly Love discovered a genetic mutation that they called “the Philadelphia chromosome” in patients with chronic myelogenous leukemia, a fatal, spontaneously arising cancer of the blood.In her book of the same title, Jessica Wapner chronicles the ensuing decades of laborious scientific inquiry and industrial ingenuity that led to the discovery of Gleevec, the first drug designed to attack cancer at the genetic level. Its success in beating CML into remission and making the errant chromosome disappear has helped to revolutionize cancer research, unleashing a hunt for the genetic basis of other cancers and opening the door to comparable targeted treatments.

While the money came from drug maker Novartis,NOVN.VX -0.07% the hero of the story is Brian Druker, an oncologist and researcher at Oregon Health & Science University. His unwavering determination kept the development of Gleevec on track against formidable odds, not least of which was the fact that CML, a rare disease with fewer than 6,000 new cases annually in the U.S., seemed to hold little potential for the blockbuster sales that typically attract pharmaceutical-company investment.

Ms. Wapner tracks decades of work by scientists who often had little knowledge of one another but eventually proved that the Philadelphia chromosome was the sole cause of CML. The mutation causes separate genes to fuse and become one, producing an abnormal protein, tyrosine kinase, which causes white blood cells to proliferate uncontrollably. The resulting cascade becomes a “killing machine,” in Ms. Wapner’s phrase. Blood turns into “viscous sludge” as red cells plummet. Meanwhile, platelets become too few to make the blood clot, and severe bleeding precedes death.

Having myself received the diagnosis for CML in 1992, I can testify that it is a fairly terrifying experience. At the time there was no Gleevec in sight. Patients were prescribed the drug hydroxyurea to slow things down, but it didn’t work for long, and another common treatment, interferon, was tough to tolerate and wasn’t a long-term solution in any case. The only possible cure was a bone-marrow transplant, which carried risks—including rejection—and required a suitable donor, preferably a matched sibling. (I was fortunate to have two.)

Surprisingly, Ms. Wapner gives short shrift to bone-marrow transplantation, portraying it as the worst possible option when in fact it has saved the lives of many CML patients, including my own. She also dismisses the side effects of Gleevec as minimal. Having taken the drug as part of treatment for recurrences more than a decade after my transplant, I can attest to its unpleasantness, a reason that some patients have stopped using the drug. Resistance also develops, leading some patients to seek transplants after all.

In “The Philadelphia Chromosome,” Ms. Wapner routinely translates the complexities of science for the lay reader, notably the role of tyrosine kinase and the quest to inhibit its deadly activity. Whenever the details get to be tough slogging, she offers up straight talk to explain what it all means: “In the hunt for cancer’s underlying mechanism, finding tyrosine was like a tracker finding an animal print or a broken branch. They knew they had caught the right trail.”

The narrative picks up steam when Dr. Druker moves from the Dana-Farber Cancer Institute in Boston to a new research job at Oregon Health & Sciences University. He secures several compounds from Ciba-Geigy, the pharmaceutical company, which is also pursuing a drug. He ultimately uses the compounds to find the Holy Grail: an antibody that is able to bind to the errant protein and block its effects.

Dr. Druker found supporters among Ciba-Geigy’s scientists, but it was hardly clear coasting from there, and Ms. Wapner’s tale shifts to the often-frustrating struggle to clear the regulatory, political and financial hurdles that kept popping up. Though the lead compound of the drug that would become Gleevec was synthesized by 1990, seven years later the first phase of human trials had yet to begin.

The turning point came in 1996, after the merger of Ciba-Geigy and Sandoz created Novartis, whose new chief executive, Dr. Dan Vasella, allowed the evidence to prevail over business hesitations within the company. Once human trials were under way, the results were breathtaking: Abnormal white blood cells disappeared, and normal blood cells were not affected.

Soon the Web was abuzz with news of the drug. For patient Bud Romine, it was a miracle. “The sword that had been hanging over his neck, waiting to fall, was now gone,” Ms. Wapner writes. “He’d been waiting to die, and now he knew he was going to live.” After being fast-tracked at the Food and Drug Administration, Gleevec set a record for swift approval in 2001. Gleevec must be taken daily for life and costs about $6,500 a month, though there are programs for those who can’t afford it. From 2001 to 2011, Ms. Wapner reports, world-wide sales were close to $28 billion, and Novartis and others now offer second-generation drugs that may be more tolerable and effective.

Novartis took much of the credit for Gleevec’s success, and Dr. Vasella wrote his own 2003 book about its development, “Magic Cancer Bullet.” Dr. Druker, who did not profit from the drug, did not seem to get the credit he deserved. Thanks to Ms. Wapner, he gets it now. Dr. Druker and Dr. Vasella, since retired from Novartis, strike a conciliatory note at the end of Ms. Wapner’s account, stressing the importance of collaboration between academia and industry, especially when research funding is limited. “The drug companies aren’t evil,” Dr. Druker says from his vantage as a university scientist. “They make drugs, and we should help them.”

Ms. Landro, a Journal editor and columnist, is the author of “Survivor: Taking Control of Your Fight Against Cancer.”