Chemical Biology Teamwork

The National Institutes of Health’s National Cancer Institute (NCI) has been a player in the drug development arena for more than 50 years, but its use of chemistry in this effort has trailed its use of biology. With the recently launched Chemical Biology Consortium (CBC), NCI plans to change that and kick its drug development game up a notch.

In the past, NCI’s decentralized drug development efforts have been inefficient, said James H. Doroshow, director of NCI’s Division of Cancer Treatment & Diagnosis (DCTD), speaking at the CBC launch in August. With the launch of this program, NCI is now merging its drug programs into a single pipeline to increase the flow of early-stage molecules into drug development, Doroshow said. CBC will be part of NCI’s Experimental Therapeutics program and run out of NCI’s Frederick, Md., facility. It will be managed by the consulting company SAIC.

The CBC program has been in the works for two years and has an initial partial-year budget of approximately $9 million, which represents new funding rather than a reshuffling of existing NCI resources, says Joseph E. Tomaszewski, deputy director of DCTD. The funding comes from the Office of the Director of NCI and should increase as long as the director considers it to be an important program, which the current director, John E. Niederhuber, does.

CBC will play to its strengths by focusing on pediatric and rare cancers that the private sector has inadequately addressed. “CBC is not here to replicate pharmaceutical companies,” Doroshow said. “We’re not going to shy away from risks and long time horizons.”

To usher compounds through the drug discovery process, CBC will harness the capabilities of 12 member centers. These contractors—not grantees—include academic centers, nonprofit research institutes, and one contract research organization. In addition, the NIH Chemical Genomics Center is a consortium member.

Making CBC a contracts program opens up the possibility for outside principal investigators to submit proposals, Doroshow said. If those ideas are deemed priorities during peer review, outside investigators become part of the consortium and are given access to the members’ facilities. Outside investigators will have to sign the CBC intellectual property agreement, which allows data to be shared among all the consortium members.

“As a chemist at NIH, I’m excited to see that chemistry will play a central role in this new initiative by NCI,” says Sanjay V. Malhotra, director of CBC’s Chemical Diversity Division, whose lab will coordinate chemistry efforts of the CBC program.

Project teams will shepherd potential therapeutics through a multistage discovery process. Projects, which can be proposed by extramural or intramural researchers, can enter this process at any stage. Graduating from one stage to the next will require meeting carefully laid out milestones.

Each member facility was selected in a competitive process on the basis of its expertise in chemistry and screening as well as its ability to bring varied strengths to the program. The centers are categorized as screening centers, chemical diversity centers, and specialized application centers.

For example, the Small Molecule Discovery Center at the University of California, San Francisco, is a specialized application center that offers expertise in fragment-based discovery, in which potential drugs are stitched together piece by piece. At the launch, James A. Wells, director of the center, said that this approach gives them a ladder to reach and harvest “high-hanging fruit,” targets that have not yielded to high-throughput screening methods.

SRI International, another consortium member and a nonprofit research institute in Palo Alto, Calif., is a screening center that focuses on tumor microenvironments, said Lidia Sambucetti, senior director of cancer research at SRI. Using three-dimensional tissue models, they study hypoxia, signaling, and apoptosis.

Two facilities at the University of Pittsburgh were selected as CBC members, the Chemical Diversity Center headed by Donna M. Huryn, and the Specialized Application Center led by John S. Lazo, who is also the director of Pitt’s Drug Discovery Institute. These facilities are capable of conducting both biology- and chemistry-driven projects. The Drug Discovery Institute is home to one of the world’s largest zebrafish facilities, where they use zebrafish embryos as biosensors in whole-organism assays.

The University of Minnesota Chemical Diversity Center brings particular strengths in natural products to the consortium. For example, the center already has two clinical candidates derived from natural products—minnelide, a water-soluble pro­drug of triptolide, for pancreatic cancer and a genetically engineered biologic that selectively targets chemorefractory breast, lung, and prostate cancers, the center’s director, Gunda I. Georg, said at the launch.

These and the other CBC facilities will soon get cracking on program-specific projects. CBC has already received its first batch of proposals, which were due on Sept. 15. Of the 55 proposals, 38 came from CBC members and 17 were from external researchers, according to Tomaszewski. He expects that the proposals will be reviewed within about a month. Future CBC proposals will be accepted quarterly with Nov. 15, Feb. 15, May 15, and Aug. 15 deadlines.