Wellcome funds for translational research

Drs. Bruce Clurman and Cassian Yee, Clinical Research Division investigators researching novel treatments for melanoma and other cancers, are recipients of prestigious Burroughs Wellcome Fund grant awards. Each year, the pharmaceutical company gives Clinical Scientist Awards in translational research to only 10 recipients — who will each receive $150,000 annually for five years, for a total of $750,000. Clurman's award is for research on developing diagnostic and therapeutic approaches to cancers that are based on the abnormal control of cell division that occurs in diseases such as breast and colon cancers.

In tumors, there are frequent disruptions in pathways that regulate cell division. This deregulated cell-cycle control plays a fundamental role in the development of cancer. Because these pathways regulate the ways that cells divide or die in response to stimuli, they are widely considered to represent key targets for new therapeutic approaches to cancer. However, despite its great promise, progress on cell cycle-based therapy so far has been disappointing, largely due to the limited understanding of these complex pathways.

"The goal of my research is to build upon our recent advances in understanding how some of these pathways work, and to develop treatment strategies based upon specific mechanisms of cell cyclic deregulation in tumors," Clurman said. "This work is focused on a cell-cycle protein named cyclin E that plays a central role in regulating cell division."

Clurman's lab will create cell-based and mouse models that mimic cyclin E-associated cancers and use these models to identify gene targets and drugs that are toxic to cells and cancers with these mutations.

The researchers also will determine whether antibodies that report on the activity of these pathways can be developed as diagnostic and prognostic markers for patients with cyclin E-associated cancers.

Cyclin E was discovered in the lab of Dr. Jim Roberts, director of the Basic Sciences Division.

"The Burroughs Wellcome grant is enormously important for this type of research," Clurman said. "The basic science that underlies this project is typically funded by traditional sources, but translating the work to clinical applications requires discovery-based approaches that are 'high-risk' by their very nature in terms of return on investment, and thus hard to initially fund."

Yee's award is for his study of adoptive immunotherapy, specifically strategies to augment the antigen-specific T-cell response in patients with melanoma and other solid tumors. Treatment of patients with advanced melanoma and other solid tumors has been difficult due to infrequent responses and short remissions. Manipulation of the immune system — in this case, the T-cell component — offers the promise of minimal toxicity and long-term immune protection against tumors, Yee said.

Initial studies at the Center in the use of antigen-specific T cells — expanded and then adoptively transferred to the patient in a process known as adoptive T-cell therapy — showed evidence of clinical responses in patients who had failed other therapies. The clinical studies funded by the Burroughs Wellcome grant are designed to address some of the limitations of adoptive T-cell therapy that were identified in these initial studies and to improve its tumor-fighting ability.

"We seek to understand the reasons for the success or failure of a given approach," Yee said. "The infrastructure that we established to isolate and expand antigen-specific T-cell clones from the peripheral blood of patients for clinical trials offers us a unique opportunity to perform second- and third-generation studies to improve cancer immunotherapy."

Opportunity for exploration

In addition, pre-infusion treatment with chemotherapy or other drugs that modulate a patient's immune system may enhance the immune environment in such a way that tumor-specific T cells are more likely to expand and survive after they are infused. This strategy of 'conditioning' the patient before T-cell infusion can also be evaluated in a relevant animal model before embarking on clinical trials.

"The Burroughs Wellcome award provides a tremendous opportunity for us to explore areas of cellular immunotherapy that we would otherwise not be able to fund," Yee said. "I believe that these studies will be a catalyst for new avenues of research that will ultimately be the basis for applying for expanded sources of funding and fostering the development of new investigators."