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More than a decade after scientists decoded the human genome and promised a new era of powerful medicines, patients and physicians often find themselves asking: "Where are they?"
To be sure, doctors have gained about a dozen "targeted" cancer drugs that attack points in certain tumors to block their growth. Yet more than 500 known mutant cancer genes that drive tumors await the development of new chemical compounds that can "drug" those targets and benefit patients.
"I am a little frustrated to see how many of the discoveries that do look as though they have therapeutic implications are waiting for the pharmaceutical industry to follow through with them," Francis Collins, MD, PhD, director of the National Institutes of Health, told The New York Times last year.
Now, academic centers like Dana-Farber are stepping up to the plate.
"We're in a position to exploit our new knowledge about cancer and we want to start accelerating drug development so we can have a major impact on therapies," says Barrett Rollins, MD, PhD, Dana-Farber's chief scientific officer. "We need to start making drugs ourselves – especially therapies for rarer cancers of less interest to industry."
Over the past seven years, Dana-Farber has built a powerful drug discovery and development capability based on new integrative research centers, where biologists and chemists combine efforts to speed the discovery, evaluation, refinement, and early testing of potential treatments.
Traditionally, pharmaceutical companies seek new, experimental compounds, which come from scientists or researchers in academic research centers. In this phase, termed "drug discovery," the molecules are tested in cells and animals to produce a "lead compound," explains George Demetri, MD, senior vice president for Experimental Therapeutics at Dana-Farber.
That lead compound, in turn, undergoes much further development at the drug company, which includes synthesizing the would-be drug, extensive testing in other laboratories, and clinical trials to assess both safety and activity. Only then can it become a truly useful medicine with approval by the Food and Drug Administration (FDA), which gives a company the right to commercialize and distribute the drug for medical practice.
But this typical separation of functions has proven inefficient and a source of delays. Academic institutions, industry, and the federal government are now working to streamline the process, in part by performing functions in a different way.
Currently, the pharmaceutical industry is doing less drug discovery in its own labs and is often throttling back its drug-development efforts. "We can't leave drug discovery to the pharmaceutical sector," Demetri says.
The path a promising compound takes during years of lab, animal, toxicity, and efficacy tests is sometimes called "the valley of death" because so many would-be drugs fail.
Bringing a drug to market requires approximately 12 years, according to one estimate, with an average cost of $1.2 billion. Dana-Farber has the expertise and resources to boost the odds of picking winners. "Our scientists have knowledge about diseases and patients that helps them predict how prototype drugs will fare in testing," says Demetri.
Dana-Farber's drug development program grew out of a strategic planning process, undertaken in 2003, which spawned more than a dozen integrative research centers here. Some centers have specific roles in moving laboratory discoveries through the stages of drug development, ideally leading to the first clinical trials in patients.
These are some of the centers and their specialized functions:
C-NExT is the newest of Dana-Farber's integrative research centers. "Our mission is to accelerate the ‘bench-to-bedside' transition," says Nancy Kohl, PhD, a veteran scientist with more than 20 years of pharmaceutical industry research and now the head of research at C-NExT. "We want to find the right drugs for the right patients."
Her team collaborates closely with the Early Drug Development Center, where physicians treat patients enrolled in phase I trials. "Often, observations made in the clinic will benefit from follow-up in further preclinical studies [at the C-NExT and LFIC]," Kohl says.
While Dana-Farber is committed to moving prototype drugs along their journey, it is not becoming a drug company. Pharmaceutical companies have the expertise and resources to turn compounds into FDA-approved products and bring them to market.
Dana-Farber has agreements with leading pharmaceutical corporations, such as Novartis, Sanofi, and Merck, to commercialize promising discoveries from Dana-Farber labs. In addition, the Institute's Office of Research and Technology Ventures can help Dana-Farber investigators patent novel compounds and license them to drug companies on a case-by-case basis.
Some of these firms are startups founded by Dana-Farber researchers. For example, Bruce Spiegelman, PhD, and his colleagues recently discovered a natural hormone that links exercise to certain health benefits, but the hormone will require a lot of pharmacologic work before becoming a drug ready for human testing.
Spiegelman and scientists from other research centers founded Ember Therapeutics, a company to carry out that development work. Other examples are Tensha Therapeutics, founded by Jay Bradner, MD, and Acetylon Pharmaceuticals, founded by Bradner, Kenneth Anderson, MD, and others to develop drugs called HDAC inhibitors.
"Investigator-started companies have become a tried-and-true way in the last 25 years to move compounds into development," says Rollins.
Spiegelman says that he's "somewhat skeptical" about how much drug development work can be taken on by Dana-Farber. "We have the best labs in the world, but they're not here to specifically make a drug."
"Bruce is right," agrees Rollins. "But that's the difference between our basic discovery labs and the integrative centers. We are now hiring people who do this [preclinical research on novel compounds] for a living." Kohl, for example, worked at Merck for 20 years in cancer drug discovery before accepting her position at the C-NExT lab in 2009.
Discovering cancer targets and molecular lead compounds to attack them is a traditional Dana-Farber strength; fashioning them into usable proto-medicines that might work in the real world is a newer internal goal.
"What's been missing within our four walls is a robust generator of drug-like compounds," Rollins explains. "In order to contribute to new drugs, we need to have active chemists on-site." Their work requires highly specialized resources similar to industrial labs, with safety hoods, sophisticated air-handling equipment, and other requirements.
Retrofitting existing labs at Dana-Farber for chemists is prohibitively expensive, says Rollins, but the Institute recently leased space in a new facility being built near Dana-Farber's main campus. A section of this space, slated to open in 2014, will house chemists and other investigators to expand this initiative.
In the meantime, Dana-Farber has established a chemical biology program that will move into the new building when it's completed. The chemists have enjoyed quick success, generating compounds that are already moving into clinical trials.
As it rises to meet the drug development challenge, says Demetri, Dana-Farber is remaking its image of itself.
"We are part of an ecosystem – bioengineering and enablers of technology getting turned into new medicines," Demetri explains. "We don't live in that world alone. We're reaching out to clients, customers, and collaborators to say, ‘How can we do this better?' We're trying to accelerate progress through the many strengths of our faculty and our Institute."
Paths of Progress Spring/Summer 2012 Table of Contents