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In developing new cancer drugs, secrecy is the norm. Researchers routinely guard the details of promising laboratory findings closely until they're published and patented, and pharmaceutical companies similarly keep quiet about their own discoveries.
But, taking a cue from the open-source movement in the computer software industry – in which companies make software available free online for consumers and developers to try out and modify – some scientists are beginning to advocate such an approach to early drug discovery.
They say that freely distributing research results and drug prototypes widely to others in the field, a process also known as "crowd sourcing," can help speed the translation of a molecule into a medicine.
One scientist who fervently believes so is Dana-Farber's James Bradner, MD, who has been testing this radical approach for the past two years. He says it has accelerated the development of a potential new cancer drug.
Motivated by the plight of a young fireman dying from a rare, incurable cancer, Bradner and his colleagues at Dana-Farber created an experimental compound that showed promise for blocking the growth of his cancer, called NUT midline carcinoma. The compound erases a component of cellular memory, in effect causing the cancerous cells to become non-cancerous tissue.
In 2010, Bradner's lab began sending versions of the compound to scientists all over the world, asking for their insights about other types of cancer that might respond to such a therapy.
"Traditionally, you have a big discovery, you keep it to yourself, and you publish a paper with your lab," Bradner says. "Here, we wanted to get the word out so others could improve the molecule and find different applications for its use."
Within a year, this open-source approach yielded a prototype drug known as a bromodomain inhibitor. Bradner dubbed it "JQ1" in honor of chemist Jun Qi, PhD, a senior research scientist in the lab who synthesized the original compound.
The year of working openly, Bradner says, "was a social experiment to see if people would be receptive to this style of research. Could a drug emerge on the other side? Would we better understand the subsets of cancer patients who might respond? In both cases, the answer is clearly 'yes.'"
The new compound came too late to help the fireman, and it hasn't yet reached clinical trials in humans. But it has been licensed by Dana-Farber to Tensha Therapeutics, a Boston-based company created by Bradner for the specialized science needed to make the compound into a drug ready for human trials.
Meanwhile, further research by Bradner and others suggests that JQ1 and other bromodomain inhibitors may well find uses in treating other types of cancers and leukemias.
Since late 2010, Bradner's lab has sent the JQ1 molecule to more than 200 laboratories worldwide, including six competing pharmaceutical companies, four foreign governments, and more than 60 labs in the U.S. Now, Bradner says, "people have open access to this molecule so they can learn something about whatever it is that they are studying."
This is in contrast to the typical model. "The identity, and in many cases existence of, early prototype drugs developed in pharmaceutical companies are almost never shared with the outside world," Bradner says.
Of course, giving out the drugs freely to other laboratories risks that a competitor will use them to make discoveries and publish papers on them alone. So far, this has only rarely occurred. More commonly, scientists unknown to the Bradner group request a sample of JQ1 to test a hypothesis.
Recently, scientists at the Cold Spring Harbor Laboratory in New York experimented with the JQ1 compound to see if it might be effective in leukemia. Their research showed that it was. Bradner admits that some colleagues in his laboratory were momentarily disappointed, as they were pursuing the same discovery.
"But we believe in this open innovation model, and it was a privilege to collaborate with the Cold Spring Harbor laboratories," says Bradner. "As we informed their work in leukemia, they helped our work in multiple myeloma."
Bradner is convinced that JQ1 and its successors are evolving more rapidly because of this collaboration. "Over the next year, data from our group, alongside the findings of leading laboratories in three major types of cancer, will reveal a path forward for drug-like derivatives of JQ1 in the clinic," Bradner says. "The pace of this research simply could not be accomplished by one laboratory alone."
In the three years he has been at the Institute, says Bradner, "We have realized what a special place Dana-Farber is for the science of drug discovery. At every step in the drug development process, we have one or more world leaders working here."
By working together, the scientific and industrial communities hope to accelerate the slow pace at which new targeted drugs, based on discoveries of the Human Genome Project, are reaching patients.
Many of the recently found targets in cancer cells – genetic malfunctions that fuel the cancers – have appeared "undruggable," or difficult to hit with designer compounds. "We know of 500 mutated genes that contribute to cancer," notes Bradner. "But we have only about a dozen that may be targeted by therapeutic agents."
In fact, the bromodomain protein, which Bradner's group found was driving NUT midline cancers, initially looked undruggable. But Bradner and Qi came up with a strategy to disable the bromodomain target, and designed a compound for the purpose: This was the birth of JQ1.
Next, Bradner went to the bedside of the young firefighter who was dying of the disease. He asked the patient if he would give consent for research on the tumor cells that were being drained from his lung every day. "We approached him as a collaborator," says the physician-scientist. The man agreed.
The cancer cells made a crosstown trip to the Boston waterfront, home of Dana-Farber's Lurie Family Imaging Center, where director Andrew Kung, MD, PhD, put them into mice – creating the first animal model of the midline cancer. Miniaturized PET-CT scanners showed that the compound turned cancer into noncancerous tissue – and mice treated with the chemical survived much longer than those that did not receive it.
The Bradner team set to work. Synthetic chemists made 600 variations of the compound and found a number of drug-like candidates for human testing. Advanced prototypes were patented and licensed to Tensha Therapeutics, Bradner's startup company. Others were shared with the research community, labs, and scientists who would tinker with the molecules to see if they might be effective against more-common cancers.
Over the past year, large companies have begun to develop bromodomain inhibitors of their own, while Tensha has made "remarkable progress" on JQ1 and the next-generation drug, according to Bradner.
"Within two years, I expect at least two bromodomain inhibitors to enter clinical trials," Bradner says. "This is our dream scenario, in which discoveries made in Dana-Farber labs are translated into new experimental drugs that can be tested to benefit patients worldwide."
Paths of Progress Spring/Summer 2012 Table of Contents