March 2, 1999
Nearly 90 percent of prostate cancers -- "the typical, garden varieties," according to Johns Hopkins scientists -- are linked to a previously unsuspected but common genetic process that could be reversible. The process looks to be a fundamental one in cancer and appears in other common forms of the disease, like breast cancer.
Unlike cancers due to mutations that make structural changes in a gene, such as the colon cancers that run in families, most prostate cancer may involve a process called "gene switching," the researchers say. Switching occurs when certain members of a family of genes are switched on while others in the family shut down. "It's a process common during embryonic development," says molecular pathologist Shrihari S. Kadkol, M.D., Ph.D., one of the researchers in a study appearing today in Nature Medicine, "but we believe this is the first time anyone's definitively linked gene switching within a family of genes, with cancer."
"Most important is that someday, it's likely we can reverse switching with drugs," says molecular pathologist Gary R. Pasternack, M.D., Ph.D., who led the Hopkins research team. "This means one of the commonest cancers in men has the potential of being corrected without using typical gene therapy."
In their work, the scientists used molecular probes to highlight and compare the gene activity in cancer patients' normal prostate tissue with that of their tumors. The investigators found clear evidence that a gene called pp32 was switched on in normal cells but generally switched off in cancer cells. Earlier studies by the team showed pp32 acts as a suppressor and keeps cells from turning malignant.
Yet close relatives of the gene, to the researchers' surprise, act like pp32's genetic evil twins and encourage tumor growth. The pp32r1 and pp32r2 genes are present and turned on in perhaps 90 percent of the prostate cancers the team studied.
"We first thought pp32 had just mutated," says Kadkol, "but the types of differences between it and the variant genes told us this wasn't the case." The researchers say switching could be a fundamental process in cancer, and they've already linked it with common forms of breast cancer. "In the breast cancer patients we've examined," says Kadkol, "we saw this same pp32 switching pattern."
"If we can understand how the switching process works, what controls it," adds Pasternack, "we can potentially reverse it. That's our next task." If their work goes smoothly, he adds, they could screen and find drugs for this purpose within two years. Then the candidate investigational drug would undergo the usual FDA-sponsored tests in people.
"We also believe this work may have a role in diagnosis or in predicting disease outcome," says Pasternack. "Prostate specific antigen (PSA), the present common screen for prostate cancer, doesn't always tell the complete story or, particularly in older men, doesn't let us make a clear prognosis. This might help."
The prognostic studies are already underway as part of a congressionally-sponsored project with the Army to hasten select basic research into clinical applications. The reported study was funded by a grant from the National Cancer Institute. A patent is pending on the technology involved in the study. Other researchers are Jonathan R. Brody, Jining Bai, Ph.D., and Jonathan Pevsner, Ph.D.
Related Web sites: http://pathology.jhu.edu/research_programs (molecular pathology)