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Category Archives: Genetic Medicine

Foundation Medicine: Personalizing Cancer Drugs

It's personal now: Alexis Borisy (left) and Michael Pellini lead an effort to make DNA data available to help cancer patients. Credit: Christopher Harting

Michael Pellini fires up his computer and opens a report on a patient with a tumor of the salivary gland. The patient had surgery, but the cancer recurred. That's when a biopsy was sent to Foundation Medicine, the company that Pellini runs, for a detailed DNA study. Foundation deciphered some 200 genes with a known link to cancer and found what he calls "actionable" mutations in three of them. That is, each genetic defect is the target of anticancer drugs undergoing testing—though not for salivary tumors. Should the patient take one of them? "Without the DNA, no one would have thought to try these drugs," says Pellini. 

Starting this spring, for about $5,000, any oncologist will be able to ship a sliver of tumor in a bar-coded package to Foundation's lab. Foundation will extract the DNA, sequence scores of cancer genes, and prepare a report to steer doctors and patients toward drugs, most still in early testing, that are known to target the cellular defects caused by the DNA errors the analysis turns up. Pellini says that about 70 percent of cases studied to date have yielded information that a doctor could act on—whether by prescribing a particular drug, stopping treatment with another, or enrolling the patient in a clinical trial.

The idea of personalized medicine tailored to an individual's genes isn't new. In fact, several of the key figures behind Foundation have been pursuing the idea for over a decade, with mixed success. "There is still a lot to prove," agrees Pellini, who says that Foundation is working with several medical centers to expand the evidence that DNA information can broadly guide cancer treatment.

Foundation's business model hinges on the convergence of three recent developments: a steep drop in the cost of decoding DNA, much new data about the genetics of cancer, and a growing effort by pharmaceutical companies to develop drugs that combat the specific DNA defects that prompt cells to become cancerous. Last year, two of the 10 cancer drugs approved by the U.S. Food and Drug Administration came with a companion DNA test (previously, only one drug had required such a test). So, for instance, doctors who want to prescribe Zelboraf, Roche's treatment for advanced skin cancer, first test the patient for the BRAFV 600E mutation, which is found in about half of all cases.

About a third of the 900 cancer drugs currently in clinical trials could eventually come to market with a DNA or other molecular test attached, according to drug benefits manager Medco. Foundation thinks it makes sense to look at all relevant genes at once—what it calls a "pan-cancer" test. By accurately decoding cancer genes, Foundation says, it uncovers not only the most commonly seen mutations but also rare ones that might give doctors additional clues. "You can see how it will get very expensive, if not impossible, to test for each individual marker separately," Foundation Medicine's COO, Kevin Krenitsky, says. A more complete study "switches on all the lights in the room."

So far, most of Foundation's business is coming from five drug companies seeking genetic explanations for why their cancer drugs work spectacularly in some patients but not at all in others. The industry has recognized that drugs targeted to subsets of patients cost less to develop, can get FDA approval faster, and can be sold for higher prices than traditional medications. "Our portfolio is full of targets where we're developing tests based on the biology of disease," says Nicholas Dracopoli, vice president for oncology biomarkers at Janssen R&D, which is among the companies that send samples to Foundation. "If a pathway isn't activated, you get no clinical benefit by inhibiting it. We have to know which pathway is driving the dissemination of the disease."

Cancer is the most important testing ground for the idea of targeted drugs. Worldwide spending on cancer drugs is expected to reach $80 billion this year—more than is spent on any other type of medicine. But "the average cancer drug only works about 25 percent of the time," says Randy Scott, executive chairman of the molecular diagnostics company Genomic Health, which sells a test that examines 16 breast-cancer genes. "That means as a society we're spending $60 billion on drugs that don't work."

Analyzing tumor DNA is also important because research over the past decade or so has demonstrated that different types of tumors can have genetic features in common, making them treatable with the same drugs. Consider Herceptin, the first cancer drug approved for use with a DNA test to determine who should receive it. The FDA cleared it in 1998 to target breast cancers that overexpress the HER2 gene, a change that drives the cancer cells to multiply. The same mutation has been found in gastric, ovarian, and other cancers—and indeed, in 2010 the drug was approved to treat gastric cancer. "We've always seen breast cancer as breast cancer. What if a breast cancer is actually like a gastric cancer and they both have the same genetic changes?" asks Jennifer Obel, an oncologist in Chicago who has used the Foundation test.

The science underlying Foundation Medicine had its roots in a 2007 paper published by Levi Garraway and Matthew Meyerson, cancer researchers at the Broad Institute, in Cambridge, Massachusetts. They came up with a speedy way to find 238 DNA mutations then known to make cells cancerous. At the time, DNA sequencing was still too expensive for a consumer test—but, Garraway says, "we realized it would be possible to generate a high-yield set of information for a reasonable cost." He and Meyerson began talking with Broad director Eric Lander about how to get that information into the hands of oncologists.

In the 1990s, Lander had helped start Millennium Pharmaceuticals, a genomics company that had boldly promised to revolutionize oncology using similar genetic research. Ultimately, Millennium abandoned the idea—but Lander was ready to try again and began contacting former colleagues to "discuss next steps in the genomics revolution," recalls Mark Levin, who had been Millennium's CEO.

Levin had since become an investor with Third Rock Ventures. Money was no object for Third Rock, but Levin was cautious—diagnostics businesses are difficult to build and sometimes offer low returns. What followed was nearly two years of strategizing between Broad scientists and a parade of patent lawyers, oncologists, and insurance experts, which Garraway describes as being "like a customized business-school curriculum around how we're going to do diagnostics in the new era."

In 2010, Levin's firm put $18 million into the company; Google Ventures and other investors have since followed suit with $15.5 million more. Though Foundation's goals echo some of Millennium's, its investors say the technology has finally caught up. "The vision was right 10 to 15 years ago, but things took time to develop," says Alexis Borisy, a partner with Third Rock who is chairman of Foundation. "What's different now is that genomics is leading to personalized actions."

One reason for the difference is the falling cost of acquiring DNA data. Consider that last year, before his death from pancreatic cancer, Apple founder Steve Jobs paid scientists more than $100,000 to decode all the DNA of both his cancerous and his normal cells. Today, the same feat might cost half as much, and some predict that it will soon cost a few thousand dollars.

So why pay $5,000 to know the status of only about 200 genes? Foundation has several answers. First, each gene is decoded not once but hundreds of times, to yield more accurate results. The company also scours the medical literature to provide doctors with the latest information on how genetic changes influence the efficacy of specific drugs. As Krenitsky puts it, data analysis, not data generation, is now the rate-limiting factor in cancer genomics.

Although most of Foundation's customers to date are drug companies, Borisy says the company intends to build its business around serving oncologists and patients. In the United States, 1.5 million cancer cases are diagnosed annually. Borisy estimates that Foundation will process 20,000 samples this year. At $5,000 per sample, it's easy to see how such a business could reward investors. "That's ... a $100-million-a-year business," says Borisy. "But that volume is still low if this truly fulfills its potential."

Pellini says Foundation is receiving mentoring from Google in how to achieve its aim of becoming a molecular "information company." It is developing apps, longitudinal databases, and social-media tools that a patient and a doctor might use, pulling out an iPad together to drill down from the Foundation report to relevant publications and clinical trials. "It will be a new way for the world to look at molecular information in all types of settings," he says.

Several practical obstacles stand in the way of that vision. One is that some important cancer-related genes have already been patented by other companies—notably BRCA1 and BRCA2, which are owned by Myriad Genetics. These genes help repair damaged DNA, and mutations in them increase the risk of breast or ovarian cancer. Although Myriad's claim to a monopoly on testing those genes is being contested in the courts and could be overturned, Pellini agrees that patents could pose problems for a pan-cancer test like Foundation's. That's one reason Foundation itself has been racing to file patent applications as it starts to make its own discoveries. Pellini says the goal is to build a "defensive" patent position that will give the company "freedom to operate."

Another obstacle is that the idea of using DNA to guide cancer treatment puts doctors in an unfamiliar position. Physicians, as well as the FDA and insurance companies, still classify tumors and drug treatments anatomically. "We're used to calling cancers breast, colon, salivary," says oncologist Thomas Davis, of the Dartmouth-Hitchcock Medical Center, in Lebanon, New Hampshire. "That was our shorthand for what to do, based on empirical experience: 'We tried this drug in salivary [gland] cancer and it didn't work.' 'We tried this one and 20 percent of the patients responded.'"

Now the familiar taxonomy is being replaced by a molecular one. It was Davis who ordered DNA tests from several companies for the patient with the salivary-gland tumor. "I got bowled over by the amount of very precise, specific molecular information," he says. "It's wonderful, but it's a little overwhelming." The most promising lead that came out of the testing, he thinks, was evidence of overactivity by the HER2 gene—a result he says was not picked up by Foundation but was found by a different test. That DNA clue suggests to him that he could try prescribing Herceptin, the breast-cancer drug, even though evidence is limited that it works in salivary-gland cancer. "My next challenge is to get the insurance to agree to pay for these expensive therapies based on rather speculative data," he says.

Insurance companies may also be unwilling to pay $5,000 for the pan-cancer test itself, at least initially. Some already balk at paying for well-established tests, says Christopher-Paul Milne, associate director of the Tufts Center for the Study of Drug Development, who calls reimbursement "one of the biggest impediments to personalized medicine." But Milne predicts that it's just a matter of time before payers come around as the number of medications targeted to people's DNA grows. "Once you get 10 drugs that require screening, or to where practitioners wouldn't think about using a drug without screening first, the floodgates will open," he says. "Soon, in cancer, this is the way you will do medicine."

Adrienne Burke was founding editor of Genome Technology magazine and is a contributor to Forbes.com and Yahoo Small Business Advisor.

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Foundation Medicine: Personalizing Cancer Drugs

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Program in Cellular and Molecular Biology at Simon Fraser University – Video

24-12-2011 12:55 Research interests include cellular neuroscience, developmental biology and genetics, immunology, microbiology and lipid transport, in both plants and animals. Molecular mechanisms that control cell structure and function as well as the organization of cells into complex organs or organ systems within single organisms. How do the cells respond to stress? How is the expression of key proteins regulated? How do cells use energy ? How do cells make your heart beat - your brain think - your eyes see? How does the action of individual cells translate into working organs and systems? How do the cells organize themselves into complex organs or organ systems in such a way that the whole is greater than the sum of its parts? How can certain organisms survive in an extreme environment? Further career and educational opportunities: The Cells, Molecules and Physiology stream prepares students for careers in Medicine, Diagnostics, Biotechnology and Pharmaceuticals, Cancer Research, Bioengineering, Forensics, Science Writing, Science Education, Genetic Counseling, Dentistry, Veterinary Medicine, consulting in the areas of toxicology, fisheries, and more. Practical knowledge Learn about the science behind the headlines: understand the new developments in how we identify and treat illnesses, modify crops for drought tolerance and higher nutrition, clone cells and organisms. This video includes interviews with graduate students and professors in Biological Sciences at SFU.

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Program in Cellular and Molecular Biology at Simon Fraser University - Video

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Cracking the Genetic Code

Biomedical research lost one of its titans with the death of Marshall Nirenberg, the Nobel Prize-winning biochemist who, with the help of colleagues at the National Institutes of Health (NIH) and elsewhere, cracked the genetic code in 1961. His experiment showed how RNA transmits encoded information in DNA and directs the building of proteins (the National Museum of American History owns a copy of his chart of 64 3-letter combinations describing all possible amino acids, the building blocks of proteins, and the NIH has an excellent virtual exhibit about Nirenberg's work).

Nirenberg was the first federal employee to win the Nobel Prize in physiology or medicine. It made him an instant celebrity. While tempted by job offers in academe and elsewhere -- they were surely his for the asking -- Nirenberg ended up spending his entire career at the NIH. He said he just couldn't see giving up the freedom they gave him to pursue his research.

I had the privilege of meeting this quietly modest man a couple of times, as NIH is just up the pike from the museum in downtown D.C. That's Rockville Pike, the spine of the so-called I-270 biotech corridor, but Nirenberg worked there long before the region acquired its current moniker. The area's great research organizations, like NIH and the nearby National Institute of Standards and Technology -- which has garnered its own share of Nobel Prizes -- are cornerstones of the new technology corridor. But they rest on over a century of institution building, both private and public.

Federal science agencies tend to treasure their Nobel laureates. It's the sort of thing that private industrial research labs used to do, but say they can no longer afford. We are fortunate indeed that government agencies like NIH continue to do the far-horizon research that launches and sustains our nation's high-tech networks, the incubators of new technologies. A clear case, in my view, of government money well spent.

Image: Nirenberg performing an experiment in his lab c. 1962/National Institutes of Health.

This post also appears on the Smithsonian's O Say Can You See? blog, an Atlantic partner site.

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Cracking the Genetic Code

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Research helps demystify a genetic disorder

Dr. Elizabeth Berry-Kravis has spent much of her career focused on Fragile X, a genetic condition involving a mutation on the X chromosome that causes cognitive disabilities, behavioral issues and other problems.

New medications and therapeutic interventions have revolutionized life for people with the syndrome over the past 20 years, but Berry-Kravis, who runs the Fragile X Clinic and Research Program at Rush University in Chicago, said the most exciting discoveries are being explored now.

She was in Houston recently for a meeting of the Fragile X Clinical and Research Consortium at Texas Children's Hospital and spoke with Chronicle reporter Jeannie Kever.

Q. Tell me a little about Fragile X. How many people does it affect, and how does it manifest?

A. The description everyone uses is, it's the most common inherited form of intellectual disability. It's also the most common known genetic cause of autism. Children will seem pretty normal as young babies, but then they'll present to their pediatrician with a delay in walking or acquiring other motor milestones. A delay in talking is common. They'll have ongoing learning difficulties.

In elementary school, most of the guys with Fragile X will be in special education and have occupational therapy, speech therapy. Fragile X patients have a lot of behavioral difficulties, hyperactivity, problems paying attention, sometimes more aggressive behaviors.

It occurs in about 1 in 4,000 people. The gene that causes Fragile X is on the X chromosome. Men have only one copy of the X chromosome; girls have two. In girls, the normal gene on the other X chromosome tends to make the condition milder.

Q. What are researchers looking at?

A. The research that is particularly exciting, we have a mouse that has Fragile X. The mouse brain looks very similar to the human brain (of someone with Fragile X), so we can study the mechanisms of disease in the mouse.

Now we are working on treatments to target those pathways ... to try to improve the brain cell connections. We can show that certain agents actually work in the mouse to impact different behaviors.

Some of those are being translated into humans. Now, if a patient has attention problems, we would treat it with medicine. But these new medications are targeted to the actual (behavior-causing) mechanisms.

Q. Is that a new approach?

A. It hasn't been done before in a developmental disorder, so Fragile X has become very hot in the research world. What's happening here will become a model for developing treatments for Down syndrome and autism.

Currently, three drugs are in clinical trials. We don't know really how well the drugs are going to work in people yet. We're very hopeful, but we have to remind ourselves the human is not the mouse.

If these drugs do produce improvements, and particularly if they produce cognitive improvements, which has never been done, it would be pretty earth-shaking.

Q. What does that mean for people with Fragile X and their families?

A. In the past, patients with Fragile X were very difficult. They couldn't be handled in the schools. There weren't good medications to help with their symptoms. They would be excluded from society.

They also tended to acquire very few academic skills, because people believed they weren't teachable. Now we've seen a revolution in teaching these patients. Even without the new drugs, the advances in the past 10 or 20 years about early intervention, molding education to the child ... has made a big improvement.

With the advance of behavioral drugs, we can manage the behavior with medications and therapy and educational strategies. More of my patients now are getting out of high school and getting into a job.

If we could treat the biology at least a little bit with these new medications, we would see an added bonus.

 

jeannie.kever@chron.com

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Research helps demystify a genetic disorder

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privacy controlled social networking to connect patients with caregivers

Via Scoop.itinPharmatics
Privacy controlled & safe social network for Healthcare launched by Jonathan Schwartz, Ex-CEO Sun Microsystems. The networks available at http://www.carezone.com  Connects Caregivers With family members and allows health-care workers share information about aging or ill parents, spouses and children
Via http://www.bloomberg.com

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SOCIAL CRM and its Impact on Pharmaceutical Industry

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