January 14, 2000

VICC joins NCI effort to create new animal models to study cancer

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Dr. Robert Coffey Jr.

VICC joins NCI effort to create new animal models to study cancer

Scientists from the Vanderbilt-Ingram Cancer Center have been selected to participate in the National Cancer Institute's new Mouse Models of Human Cancers Consortium.

The NCI announced formation of the Consortium, including 19 groups from more than 30 U.S. institutions, on Dec. 28. These groups will work separately to develop and evaluate mouse models to parallel the development and progression of human cancers of eight major organ systems — breast, prostate, lung, ovary, skin, blood and lymph system, colon and brain. They will share their findings and work together to set research priorities and overcome technological obstacles.

The selection brings $2.5 million in funding over the next five years for VICC scientists' work in mouse models for breast, prostate, colon and pancreatic cancer. More important than the money, however, is the participation that Vanderbilt will have in setting priorities for mouse model research in the coming years, said Dr. Robert Coffey Jr., Ingram Professor of Cancer Research and principal investigator in the project.

"This is an important priority for NCI director Dr. Richard Klausner," Coffey said. "The initial plan called for six centers to be selected and funded. When the 32 proposals came in, they were reviewed by a group of investigators, who awarded Vanderbilt's application the second-highest score. So we were assured a place at the table. However, Dr. Klausner was so excited about the quality of the applications and the possibilities that could emerge from this Consortium, he identified additional funds to expand the group from six to 19."

The development of mouse models of human cancer, through various sophisticated genetic engineering techniques, is critical to unlocking more of the mysteries of how cancer develops. As scientists learn more about the many genetic steps involved in the process, the goal is to use that knowledge to develop methods to cure cancer and ultimately to prevent it.

"New mouse model technology provides a unique opportunity for NCI to accelerate the tempo at which mouse models of cancer are developed by the scientific community," Klausner said in a statement. "We believe that creating a Consortium now will pay huge dividends in progress in cancer research in years to come."

The VICC's proposal is a collective endeavor involving more than 20 investigators at Vanderbilt, said Coffey. Co-principle investigators in the grant are Dr. Harold L. Moses, Benjamin F. Byrd Professor of Oncology and director of the VICC; Robert J. Matusik, Ph.D., professor of Urologic Surgery and Cell Biology; and David W. Threadgill, Ph.D., assistant professor of Cell Biology and Medicine.

The VICC's grant application focused a great deal on work with the type 2 receptor for transforming growth factor beta (TGFb) in colon, prostate and breast cancer. "We are focusing on the down-regulation or elimination of this receptor and then examining implications of such manipulations for cancer development," Coffey said.

TGFb, identified and reported by Moses' Mayo Clinic research team before he joined the Vanderbilt faculty in 1985, is a powerful regulator of cell growth. One of its primary jobs is to instruct cells not to divide. The type 2 receptor is the cellular doorway through which cells "hear" this signal.

TGFb is increasingly becoming a focus for cancer researchers. Recently, an abnormally low expression of this receptor was recently identified by VICC investigators as a marker for increased cancer risk in women with a type of benign breast disease called hyperplasia. Additional abnormalities in the TGFb signaling pathway have been linked to cancer development in these breast, prostate, colon and pancreas.

The VICC scientists have developed mouse models for down-regulated TGFb receptor expression in the breast, prostate and colon, with evidence already suggesting premalignant and malignant changes in the breast, premalignant changes in the prostate and acceleration of carcinogen-induced colon cancer, Coffey said. "Our goal is to develop and validate mouse cancer models that faithfully simulate their human counterparts," he said.

In addition, the VICC's proposal also included work in three "core labs" in the areas of pathology (Drs. Kay Washington, Roy A. Jensen and Scott B. Shappell), eicosanoid research (Dr. Jason D. Morrow and Alan R. Brash), and imaging using mass spectrometry (Dr. Richard M. Caprioli) and DNA microarray analysis (Drs. Coffey, Threadgill and Rick Haselton).

These resources can be shared by all the VICC investigators and might also be shared with other institutions' representatives in the Consortium.

The VICC project also includes a "consortium within a consortium" that will focus on the development of a mouse model for pancreatic cancer. This project is headed up by Dr. Steven D. Leach, associate professor of Surgery and Cell Biology.

The proposal also called attention to the recent formation of the Tennessee Mouse Genome Consortium — including Vanderbilt Medical Center, Oak Ridge National Laboratories, Meharry Medical College, St. Jude Children's Research Hospital and the University of Tennessee — to collaborate on work to determine the functions of genes.

"While this is an institutional grant, we cited the development of that project as a strength that Vanderbilt brings," Coffey said.

The NCI Consortium will conduct its work through two annual meetings each year, augmented by meetings of "subgroups" focused on specific areas of interest and electronic communication through a special website. "For instance, a pathology subgroup has already formed to prioritize the needs in that field to support the work of the consortium," Coffey said. "They might, for instance, articulate the need for more pathologists with expertise in comparative mouse pathology and human pathology. The NCI, in turn, might then set aside significant dollars for training people with that combined expertise."

Next year, the NCI plans to activate an Internet site with information about the Consortium, its activities and its progress.

The Consortium recently kicked off its work with a nearly three-day meeting at the NCI, attended by both Klausner and Dr. Harold Varmus, outgoing director of the National Institutes of Health, Coffey said.

"We're very excited about the opportunities that this Consortium presents," Coffey said. "It's terrific that Vanderbilt scored as high as it did. We have a very relevant molecule in the type 2 TGFb receptor — it appears to be very important in human cancers — and we have unique technologies at Vanderbilt to study the models we develop in these four common human cancers.

"It places Vanderbilt at the forefront of institutions in this important area."