When specialized technology and expertise is needed, OSUCCC – James researchers turn to the cancer center’s shared resources
BY DARRELL E. WARD
Mutations in a gene called BLM cause Bloom syndrome, a rare autosomal recessive, chromosome-breakage disorder characterized by small stature, sun-sensitivity, immune deficiency and predisposition to multiple cancers.
Joanna Groden, PhD, a molecular geneticist at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James), was part of the team that discovered BLM in 1995.
Groden has since learned much about the gene’s function and the protein it encodes. In 2009, for example, her work revealed that the BLM protein interacts with topoisomerase II, a cell cycle enzyme that untangles double-stranded DNA during DNA repair and mitosis.
She and her colleagues have also shown that the interaction of the two molecules prevents chromosome breakage that contributes to many malignancies. They have also identified phosphorylation sites on the protein that regulate its interaction with topoisomerase II and have shown that when these sites are mutated the proteins can’t interact. These findings may be important to therapy; they could be used to increase the amount of DNA damage that occurs when treating tumors with radiation or DNA-damaging agents.
To make these discoveries, Groden required advanced technologies such as proteomic assays, fluorescent and confocal microscopy and analytical cell sorting, none of which are found in the average research laboratory.
Similarly, OSUCCC – James researcher Ching-Shih Chen, PhD, a medicinal chemist in the College of Pharmacy, requires a range of specialized technologies for his research in anticancer drug design.
One novel agent of Chen’s targets glucose metabolism in cancer cells. It belongs to a new class of drugs called energy-restricting mimetic agents. Chen and his lab also developedtwo drugs, AR-12 and AR-42, that are now in phase I testing at the OSUCCC – James. AR-12 inhibits two signaling pathways important in breast, colon, lung and prostate tumors; AR-42 is a histone deacetylase inhibitor active against prostate cancer in animal models.
Developing these agents required analytical cell-sorting capabilities, microarray assays and toxicopathological evaluations of the mouse models that are an essential part of drug discovery.
The advanced technologies, methods and expertise that Chen, Groden and other OSUCCC – James investigators need are provided by 15 cancer center shared resources, each of which specializes in a particular medical or research discipline (see sidebar).
“Our shared resource directors and their staff are absolutely critical to research at the OSUCCC – James,” says Michael D. Lairmore, DVM, PhD, professor of Veterinary Biosciences and associate director for Basic Research at the OSUCCC – James.
“Our shared resources are developing the latest, greatest way to do research. They often push the envelope of their science,” he says. As experts in their field, shared resource directors help investigators better approach their science and often become partners in the research and co-authors on publications. (For a close look at the OSUCCC – James’ genomics resources, see “Deep Thinking.")
In 1999, the OSUCCC – James had six shared resources. The growth in number since then reflects the expansion of the cancer center’s research programs over the past 10 years.
“Our number one concern is to develop the shared services that support the highest-quality science,” Lairmore says. “The range of services we provide reflects the science that we do here and the needs of our investigators and research programs.”
The Behavioral Measurement Shared Resource, for example, supports investigators doing population studies. “Expertise is available for everything from how to retrieve data to how to accrue patients to a study,” Lairmore explains.
New shared resources are developed as needs change. The Pharmacoanalytic Shared Resource, for example, was added in 2004 to support the rapidly expanding OSUCCC – James Experimental Therapeutics Research Program and a growing number of investigator-initiated clinical trials.
Pharmacokinetic and pharmacodynamic analyses are now a common part of clinical trials and preclinical pharmacologic studies at the OSUCCC – James,” says Michael R. Grever, MD, professor and chair of the Department of Internal Medicine, Charles Austin Doan Chair of Medicine and co-leader of the Experimental Therapeutics Program. “These correlative studies are important for synthetic agents and natural products, as well as immune-based therapies. This unit has also been extremely helpful with investigational studies of oncolytic viruses.
“The Pharmacoanalytic Shared Resource gives us a centralized facility that offers sample procurement, processing and storage, the development and validation of bioanalytical methods, and expertise in data analysis and interpretation,” he says.
Partnerships
The OSUCCC – James developed the Pharmacoanalytic Shared Resource in collaboration with the College of Pharmacy. “We often develop shared resources in partnership with Ohio State’s various colleges,” Lairmore says. “It’s one of the advantages of being a cancer center embedded within a major university.”
In fact, OSUCCC – James investigators come from 11 of Ohio State’s 14 colleges.
“Working with multiple colleges—medicine, pharmacy, veterinary medicine, agriculture and others—brings different areas of expertise to bear on a single problem: cancer,” Lairmore says. “It allows us to synergize, to maximize the strengths of the various colleges.”
The cancer center has two shared resources in development. The new Medicinal Chemistry Shared Resource (MCSR) is being developed in conjunction with the College of Pharmacy under the direction of Ching-Shih Chen, who is the Lucius A. Wing Chair of Cancer Research & Therapy, professor of Medicinal Chemistry, of Internal Medicine, and of Urology, and a member of the OSUCCC – James’ Molecular Carcinogenesis and Chemoprevention Program.
The new shared resource integrates the disciplines of medicinal chemistry, process chemistry, computational chemistry and molecular pharmacology.
“The MCSR will serve as a platform to translate basic science findings into the design and synthesis of small-molecule agents for testing individual hypotheses, and it will expedite the application of basic research findings to the clinic,” Chen says, adding that it also will help physician scientists develop research collaborations through a partnership with Ohio State’s Medicinal Chemistry and Chemistry programs.
Also in development is the Nutrient and Phytochemical Analytic Shared Resource (NAPASR), which will provide an analytical infrastructure to support the OSUCCC – James’ “crops to clinic” research efforts. It will help investigators develop methods and techniques to quantitate nutrients and phytochemicals in foodstuffs, and to identify these compounds and their metabolites in tissue samples obtained from clinical trials and preclinical studies. NAPASR was initiated with support from the OSUCCC – James and the Ohio Agricultural Research and Development Center.
“The Nutrient and Phytochemical Analytic Shared Resource will guide the development of functional-food products for cancer prevention, monitor compliance in dietary interventions, conduct absorption and bioavailability studies and investigate the interactions of genes with nutrients and phytochemicals,” says Director Steven J. Schwartz, PhD, the Carl E. Haas Endowed Chair in the Department of Food Science, College of Food, Agricultural and Environmental Sciences, and a member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Research Program.
In addition, it will provide analytical tools for investigating the role of metabolites in cancer prevention or therapy and serve as a training facility for graduate students and postdoctoral associates. Keeping pace with emerging technologies and controlling their costs are significant challenges for a major cancer center, Lairmore notes. About 30 percent of the cancer center’s shared resources are funded by the OSUCCC – James’ Cancer Center Support Grant from the National Cancer Institute. The remaining support comes from partnerships with various University colleges and departments, and from user fees.
“Our shared resources are available to investigators throughout the Ohio State campus and at other institutions,” Lairmore says. “As we look to the future, we are reaching out to other institutions and even to industry. When it comes to rapidly changing, expensive technology such as genome sequencing and imaging technology, we are trying to create a more regional sequencing shared resource.
“The term ‘shared’ is really important for success in our shared-resources formula,” he says. “Shared responsibility and shared use translate into more efficient use and higher-quality research. And that’s what’s required if we are to defeat a disease as complex as cancer.”