Feature

Partners in Science:

The Umbrella CRADA Streamlines Collaborations Between CCR and Industry

Researchers across CCR are studying the molecular mechanisms that underlie multiple diseases. Some take as their starting point the mutations that confer genetic susceptibility in familial cancers; others may start with animal models. But the goal is the same–to prevent and treat disease by manipulating dysfunctional molecular networks. Although there are many research tools available to tease apart these networks, ultimately what is required are drugs that can be administered safely and effectively to patients. The pharmaceutical industry has a number of compounds in pipelines that are usually narrowly focused on a few target diseases. CCR has the expertise to test these compounds—alone or in combination—in robust preclinical models, as well as in the clinic. The advantages of collaboration are clear, but historically it has been difficult for individual investigators to broker the necessary negotiations with individual companies. CCR’s Office of Policy and Intellectual Property, led by Eric Hale, J.D., M.B.A., has recently entered into a new kind of agreement between CCR and AstraZeneca—an Umbrella CRADA—which has made this type of collaboration much easier.

Eric Hale, J.D., M.B.A. (left), Grace Chao Yeh, Ph.D. (center), and Li Guo, Ph.D. (right), work in CCR’s Office of Policy and Intellectual Property to adapt the Cooperative Research and Development Agreements (CRADAs) to benefit both the scientists at CCR and the companies that wish to collaborate with them. (Photo: R. Baer)

Beverly Mock, Ph.D., Head of the Cancer Genetics Section of CCR’s Laboratory of Cancer Biology and Genetics, is eager to test AstraZeneca’s inhibitor of mTOR (mammalian Target of rapamycin) in her xenograft models of multiple myeloma. In her research, she and her colleagues have recently demonstrated that a combination of the mTOR inhibitor rapamycin and an inhibitor of histone deacetylase (HDAC) has a powerful antitumor effect. Their analysis of the signaling pathways involved leads them to believe that the AstraZeneca compound may produce a similar effect, and validation of this hypothesis will be additional evidence towards their model of abnormal signaling at the root of plasma cell tumors.

W. Marston Linehan, M.D., Chief of CCR’s Urologic Oncology Branch, has already started using the AstraZeneca mTOR inhibitor in cell lines derived from a patient with Birt-Hogg-Dube (BHD) syndrome and has seen very promising results. The inhibitor could be taken into clinical trials if the drug reaches that stage of development. Independently, their research on the mechanisms of action in this hereditary kidney cancer has converged with the targets of AstraZeneca’s drug in what Linehan hopes will be "a perfect match."

Through the Umbrella CRADA mechanism, CCR is now offering companies the means to study the biological activities of compounds in the context of highly developed scientific and clinical research programs that confer the ability to ask questions that companies are not themselves equipped to study. "These signals are important in validating internally that what you have spent a lot of time and treasure developing actually has biological activity," explained Gregory Curt, M.D., AstraZeneca’s U.S. Medical Science Lead.

Beverly Mock, Ph.D. (Photo: B. Branson)

W. Marston Linehan, M.D. (Photo: R. Baer)

It is not by chance that one of the most successful Umbrella CRADAs was negotiated between CCR and AstraZeneca. Curt, the man responsible for establishing the collaboration on behalf of the company, spent 22 years at NCI, including 12 years as Clinical Director of CCR. "I know the program intimately and recognize what it can do uniquely," explained Curt. "We [pharmaceutical companies] tend to look at drugs from the prism of drugs. NCI tends to look at drugs from the prism of diseases. There is a real partnership to be gained there."

Why an Umbrella CRADA?

A standard CRADA is a written agreement between a federal research organization and one or more federal or non-federal parties (collaborators) to work together as partners on a research project of mutual interest (see "CRADA History"). Until recently, CRADAs at NCI have all been handled on an individual basis. An investigator conceives an idea (which he or she would discuss with a company representative), develops a research plan, and works with NCI’s Technology Transfer Center to develop the proposed agreement. This agreement is subject to review by an NIH-wide CRADA subcommittee to ensure that issues such as fair access and conflicts of interest are handled appropriately. This process can take up to a year and can create inconsistencies even across different CRADAs with the same company.

"I am not a lawyer, nor a technology transfer guru," explained Linehan, although he nonetheless sometimes found himself sitting down with companies to allay misplaced fears of government obstacles to collaboration with industry. "Once you have that out of the way, it’s fine," he added, noting that when all you want to do is make progress scientifically, there are far fewer barriers than most companies imagine. "But the process takes a long time, and if you are trying to do this for each company, it slows you down and slows you down, and you just give up after a while."

To streamline the CRADA process for all parties concerned, Hale and his colleagues Grace Yeh, Ph.D., and Li Guo have taken it to a new level. A first of its kind for the federal government or industry, the Umbrella CRADA is an agreement designed to permit large-scale collective partnering with industry. "These Umbrella CRADAs represent an attractive new way for CCR to collaborate with industry," explained Hale. Instead of a single laboratory negotiating the specific use of a single compound, the CCR Director’s Office obtains access to an entire pipeline of compounds for more broadly stated purposes. Under the Umbrella CRADA, individual projects are submitted by CCR investigators in the form of research proposals that are approved by the company. With the legalities attended to, the focus returns to the science.

Advancing Clinical Science

Linehan has devoted 27 years to studying the genetic basis of urologic cancers (see "A War on Kidney Cancer" in Vol. 1, No. 1 of CCR connections). He and his colleagues work with families of patients with rare mutations that lead to diseases like von Hippel-Lindau (VHL) and Birt-Hogg-Dube (BHD) syndromes. While treating these rare cases, the Linehan team also uses the knowledge it gains from studying these unique patient populations with known genetic predispositions to kidney cancer to develop better treatments for both familial and sporadic forms of the diseases. "We never promised the families that we would find the genetic basis for their disease," said Linehan. "So you can imagine the thrill it was both for our research team and for the patients when we succeeded."