Crowdsourcing Therapies for Rare Cancers

March 2012
James E. Bradner

Biomedical science has been quick to emulate the open-source model, derived from software development, at least in some spheres. It is hard, however, to imagine an open-source model for drug discovery. After all, the pharmaceutical industry is motivated largely by profit, which is one reason why, in the United States, the FDA’s Office of Orphan Products Development offers additional incentives to the industry. And where’s the profit in something you can’t lock up? Some laboratories, however, are bucking the trend, few more so than James E. Bradner’s group at the Dana-Farber Cancer Institute, Harvard Medical School.

'In academia, we have the flexibility of picking our targets based on how challenging they are, how game-changing they might be.'

Bradner has successfully used open-source approaches to tackle cancer, motivated by a reasonably simple observation. “The cellular operating system that underlies cancer,” he tells Science Watch, “is controlled by a very few master regulatory factors, and by and large there are no drugs for these proteins.” The pharmaceutical industry has described these master factors—Ras, Myc, p53—as undruggable. Bradner sees things differently. “No target is undruggable. In fact, the term ‘undruggable’ just means it hasn't been drugged yet.”

Blocking BRD4

His lab’s breakthrough is a little molecule called JQ1, named for Jun Qi, the chemist in the Bradner laboratory who made it. The molecule is specifically designed to interact with a molecule called BRD4, the gene for which is implicated in several kinds of cancer. BRD4 is associated with chromatin binding during DNA copying, and seems to play a role in the control of cell division. In some types of cancer cells, Bradner explains, proteins that contain a bromodomain receptor seem to be a kind of bookmark, “a Post-it note placed around the genome as a reminder to the cell, through cell division, exactly which software to reboot. It tells the cell: ‘I’m cancer; I should keep growing’.” JQ1 blocks BRD4 and prevents the Post-it notes from sticking. But does it cure cancer?

To quickly explore the activity of JQ1 in numerous types of cancer simultaneously, Bradner decided to just mail samples of JQ1 to his friends, “to see how the molecule behaves.” The results were impressive, and very exciting. In a mouse model of human NUT midline carcinoma, a very rare and fatal cancer that is “addicted to BRD4,” the drug stopped the growth of the cancer. In four different models of cancer, mice that got the drug lived.

Selected, recent papers from James E. Bradner and colleagues,
including bromodomain inhibition and other topics
(Listed by citations)
Rank Paper Citations
1 J.E. Bradner, et al., “Chemical phylogenetics of histone deacetylases,” Nature Chem. Bio., 6(3): 238-43, March 2010. 46
2 P. Filippakopoulos, et al., "Selective inhibition of BET bromodomains," Nature, 468(7327): 1067-73, 23 December 2010. 44
3 A. Yoda, et al., “Functional screening identifies CRLF2 in precursor B-cell lymphoblastic leukemia,” PNAS, 107(1): 252-7, 5 January 2010. 32
4 J.E. Bradner, et al., “Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease,” PNAS, 107(28): 12617-22, 13 July 2010. 12
5 J.E. Delmore, et al., "BET bromodomain inhibition as a therapeutic strategy to target c-MYC," Cell, 146(6): 903-16, 16 September 2011. 2
6 J. Zuber, et al., "RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia," Nature, 478(7370): 524-8, 27 October 2011. 2

SOURCE: Web of Knowledge, Thomson Reuters

 

At this point, Bradner says, a pharmaceutical company would probably keep this a secret until they had turned a prototype drug into an active pharmaceutical substance. “And so we did the opposite.” They published the details, including the chemical pathway, and offered samples to all comers. (See adjoining table, paper #2.) “We basically tried to create the most competitive environment for our lab as possible,” Bradner jokes. With great success.

Going Public

Results streamed in from more than 70 laboratories, academic and commercial, each with their own special interests. Leukemia cells turn back into normal white blood cells. Mice with multiple myeloma, an incurable bone-marrow cancer, respond dramatically. And not just cancers. Mice exposed to the molecule that prompts sudden death due to sepsis survive, whereas mice who do not receive bromodomain inhibitors die.(See table, #4 and #5, and also E. Nicodeme, et al., Nature, 468[7327]: 1119-23, 2010). JQ1 is clearly very interesting.

Bradner has two essential qualifications for the approach he is pioneering: he is both a practicing physician and a chemical biologist. He graduated medical school in 1999, right around the time that the FDA approved Gleevec (imatinib) for the treatment of chronic myeloid leukemia. Gleevec was the first of a new class of anti-tumor drugs aimed at proteins specifically peculiar to cancer cells, rather than non-specifically killing all rapidly growing cells.

“As a doctor, I have only known the era of targeted therapy.” Bradner says. And he was disappointed that since that time, such drugs have not really established themselves as cures for cancer. “Cancer cells seem able to respond to targeted therapeutics but develop rapid resistance via the pathway that is being targeted, either through mutation or by activating a second growth pathway.” And the pharmaceutical companies didn’t seem to be interested in difficult targets, or uncommon tumors.

Bradner the biochemist wants to understand cancer and explore the field his lab has opened up, putting others on new roads to therapy. The breakthrough there is not the science but the strategy.

“Pharmaceutical companies think about the market, the population, and the clinical niche for a drug, to ensure that they can sell the molecule after investing the effort in creating a drug” Bradner tells Science Watch. “In academia, we have the flexibility of picking our targets based on how challenging they are, how game-changing they might be. We select our targets based on proteins that we perceive sit at the very core of the cancer growth signalling pathway.”

Targeting the Bromodomain

So instead of targeting master proteins like Myc, as Gleevec does, they picked on the bromodomain, which is key to the functioning of several proteins that interact with Myc. And it worked. JQ1 and other compounds from Bradner’s lab are now being turned into therapeutic drugs with good prospects. And the drug companies are watching. In fact, Bradner says, whereas a couple of years ago it would have been very difficult to propose a bromodomain discovery platform in a drug company, he suspects that since the publication of their research “many drug companies have invested heavily in studying bromodomains”. Which means they see it as worthwhile.

Does the thought of others profiting from this open-source approach worry either Bradner or his funders? After all, many universities derive a substantial income from discoveries they’ve licensed. Bradner seems genuinely puzzled by the question, as if it has never before come up, before agreeing simply that from the university and funders alike, “feedback has been very positive..”

Research on JQ1 has split now into three components: learning more about cancer biology; drug-like derivatives; and transferring the paradigm to other “undruggable” targets. One suspects that Bradner the physician regards the road to therapeutics as very important, but not all that interesting, while Bradner the biochemist wants to understand cancer and explore the field his lab has opened up, putting others on new roads to therapy. The breakthrough there is not the science but the strategy.

“For us this was a social experiment, an experiment in what would happen if we were as open and honest at the earliest phase of discovery chemistry research as we could be.”

Dr. Jeremy Cherfas is Senior Science Writer at Bioversity International, Rome, Italy.

The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.