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Cancer Grants Build Bench-Bedside Links
Researchers across the Harvard medical community are teaming up to bridge basic and clinical science in hopes of accelerating progress against a pair of common and often deadly malignancies, skin and breast cancer.
The Dana-Farber/Harvard Cancer Center has two Specialized Programs of Research Excellence sponsored by the National Cancer Institute: Thomas Kupper (above) directs the skin cancer SPORE and J. Dirk Iglehart directs the SPORE in breast cancer. Photos by Graham Ramsay
Two multi-institutional collaborations administered through the Dana-Farber/Harvard Cancer Center are funded through the National Cancer Institute SPORE (Specialized Programs of Research Excellence) initiative, which aims to speed into clinical practice novel ideas that have the potential to reduce cancer incidence and mortality and to improve survival and quality of life. Each DF/HCC SPORE has a five-year grant of approximately $15 million.
Disease-fighting SPOREsNCI's first SPORE in skin cancer, and the only one fully funded to date, was awarded in October 2001 to a Harvard-wide consortium led by principal investigator Thomas Kupper, the Thomas B. Fitzpatrick professor at HMS, the chair of Dermatology at Brigham and Women's Hospital, and the director of the Center for Cutaneous Oncology at DFCI. Coprincipal investigators are Michael Atkins, HMS associate professor of medicine at Beth Israel Deaconess Medical Center, and Frank Haluska, HMS assistant professor of medicine at Massachusetts General Hospital.
The breast cancer SPORE, one of nine nationwide, was awarded in October 2000 to a group directed by J. Dirk Iglehart, the Anne E. Dyson professor in women's cancers at HMS and the Department of Surgery at BWH. It includes investigators from all HMS-affiliated hospitals and HSPH.
One key aspect of the SPOREs' strength is the way the programs bring together scientists who would otherwise be unlikely to collaborate, and possibly even unaware of each other's work. Every major project within a SPORE--the skin SPORE has five and the breast SPORE seven--must have one principal investigator engaged in laboratory research and one involved in clinical studies.
The programs "are very focused on translation of basic biological findings into clinical practice, or conversely, taking clinical observations and explaining them in the basic lab," Iglehart said.
In addition to these major projects, each SPORE also includes career development funds to help young investigators get independent research programs going and support for "developmental projects" that could later become full-fledged projects if they show continued promise.
The skin cancer SPORE includes Kupper's own project in cutaneous T cell lymphoma (CTCL), a cancer that first appears as an innocuous-looking skin rash and is frequently ignored until it is widely disseminated and effective treatment is difficult. The other projects are aimed at melanoma, the deadliest skin cancer. A major theme is immunology: the role of immunosurveillance gone awry in CTCL and the possibility of using the immune system to fight melanoma.
"The treatment for advanced melanoma at present is totally unsatisfactory, so this is a real challenge," Kupper said.
One project will test two different techniques that use antigen-presenting dendritic cells to make a therapeutic melanoma vaccine. "There are theoretical arguments for and against both approaches, which is exactly the reason they should be compared side-by-side in a randomized trial," said Kupper. "We're fortunate to have in the Harvard system Frank Haluska, who is already doing studies with peptide-pulsed dendritic cells, and David Avigan of BID and Donald Kufe of DFCI, who developed the method for dendritic cell-tumor cell fusion. The fact that they are competing approaches speaks to the scientific curiosity and integrity of both groups--they want to find out which approach is better."
Many Steps at a TimeKupper's team is looking at molecules that confer homing properties on T cells to see whether they correlate with different stages of mycosis fungoides, the most common form of CTCL, and might be useful in diagnosis and prognosis. The group includes researchers from New England Medical Center and Boston Medical Center in addition to those from the HMS community.
"Overall, we will have many more CTCL patients than have ever been studied before," he said.
Other projects in the skin cancer SPORE involve:
- Improving risk assessment for melanoma;
- A genomewide approach to melanoma classification to evaluate whether gene expression profiling can provide additional information; and
- A study of the mechanisms of tumor response and resistance to chemo- and cytokine-based immunotherapy in high-risk and metastatic melanoma patients.
In the breast SPORE, one project involves a collaboration between Joan Brugge, HMS professor of cell biology; Myles Brown, HMS associate professor of medicine at DFCI; and investigators at the Institute of Chemistry and Cell Biology. Brugge is looking at molecular pathways responsible for invasion, metastasis, and other fundamental processes in breast cancer progression. Once the key proteins are identified, investigators at ICCB might work to identify potential inhibitors of these targets that could be developed into anticancer drugs.
In another project, Iglehart is collaborating with Emmett Schmidt, HMS associate professor of pediatrics at MGH, and Yan Geng, HMS instructor in pathology at DFCI. Last year Geng, Schmidt, and colleagues demonstrated the interdependence of the cell cycle regulator cyclin D1 and the protein Her2/Neu in breast cancer (see Research Briefs, Focus, July 13, 2001).
"Her2/Neu is the target of a very promising therapy in breast cancer using the antibody Herceptin, which is big news in cancer therapy," Iglehart said. The new data "suggested to clinicians that if you could target both molecules, you might have synergy clinically--you'd have a double whammy." Experiments in cell culture bore out that hunch and, based on the promise of these in vitro studies, the SPORE investigators received supplemental funding for a clinical trial to test a combination therapy targeting the two proteins.
Other projects in the breast cancer SPORE will:
- Attempt to improve breast cancer risk estimation and reduction by incorporating data on estrogen levels;
- Address the contribution of G2 checkpoint genes--a new class of tumor suppressor genes--to both familial and sporadic breast cancer;
- Apply recent advances in the understanding of BRCA1 and BRCA2 protein function to the clinical problem of distinguishing between disease-causing alleles and benign polymorphisms;
- Identify and evaluate molecular markers that correlate with the clinical behavior of ductal carcinoma in situ using comprehensive gene expression analysis and tissue microarrays;
- Develop transgenic mouse models for screening the efficacy of therapies directed against cyclin D1; and
- Survey the perceptions of women diagnosed with early, noninvasive breast cancer.
Each SPORE grant also supports core facilities that provide services and expertise in specific areas to projects across the SPORE. The skin cancer SPORE has biostatistics, data management, tissue banking, and immune system monitoring cores; the breast SPORE has cores covering high-risk patients and families, tissue and pathology, biostatistics, and clinical data and data management.
A New SPINIn addition to two SPOREs, the cancer institute is taking HMS for a SPIN. Funded by a $6.2 million grant over 5 years, this Shared Pathology Informatics Network project aims to create the infrastructure for a Web-based, searchable virtual repository of annotated pathology specimens. HMS is the home institution for one of two SPINs, the Consented High-performance Indexing and Retrieval of Pathology Specimens (CHIRPS) consortium. CHIRPS includes pathologists and informaticians at BID, BWH, CH, DFCI, MGH, and the UCLA Medical Center and its affiliates.