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R E S E A R C HR E P O R T S

Reversing Breast Cancer Through Gene Therapy

Lead Researcher: Paul B. Fisher

It is the bottom line in cancer treatment: Kill cancer cells but leave normal cells un-harmed. Dr. Paul B. Fisher’s research over the past several years has advanced progress toward this bottom line by identifying new cancer growth suppressor genes that lead to programmed cell death but do not alter other cellular physiology and by studying the genes for extended applications. His goal: to improve gene-based therapy of human cancer.

The latest work by Dr. Fisher, professor of clinical pathology and Michael and Stella Chernow Urological Cancer Research Scientist, extends the application of mda-7, a cancer growth suppressor gene his research team identified in 1996. The researchers showed in the earlier work that mda-7 induced growth suppression in human cancer but did not harm normal cells. The present study, reported in the November 1998 issue of the Proceedings of the National Academy of Sciences, extends the earlier research by using a replication incompetent adenovirus to express mda-7. When breast cancer cells of different p53 genotypes were infected with the newly expressed gene (Ad.mda-7 S.), growth was suppressed in vitro and the cells underwent programmed cell death, or apoptosis. Normal mammary epithelial cells infected with Ad.mda-7 S. maintained their cellular physiology.

The research showed that ectopic expression of mda-7 can inhibit tumor growth and progression in breast cancer and cervical cancer cells grown in athymic nude mice. “On the basis of the selective action of mda-7 and its potent cancer cell killing properties, this novel gene offers promise for the gene-based therapy of human cancer,” says Dr. Fisher.

Dr. Fisher first announced his research in 1994 on novel genes involved in reversing cancerous cells to harmless cells after his lab identified six such novel genes implicated in melanoma growth, differentiation, and cancer progression. Ongoing investigations in Dr. Fisher’s laboratory using Ad.mda-7 S. indicate selective apoptosis and growth suppression effects following forced expression of this gene in a wide spectrum of human cancer cell types. These include melanoma, glioblastoma multiforme, osteosarcoma, and carcinomas derived from the breast, cervix, colon, lung, and prostate. Since the different tumor cell strains contain single and multiple genetic defects, including alteration in p53, Rb and/or p16, these studies emphasize that in specific cancers, replacement of a single gene (mda-7) is all that is required to reverse the cancer phenotype by inducing apoptosis. In this context, mda-7 exemplifies a new class of cancer growth suppressor genes with potential for the targeted therapy of human cancer. The newest research is a step toward developing an efficient system for delivering mda-7 so it can be used to treat cancer in patients.

Dr. Fisher’s research is supported by grants from the NIH, the National Cancer Institute, the Department of Defense, the Samuel Waxman Cancer Foundation, and the Chernow Endowment. Other members of the research team studying mda-7 include Drs. Zao-zhong Su, Malavi T. Madireddi, Jiao Jiao Lin, Charles S.H. Young, Shinichi Kitada, John C. Reed, and Neil I. Goldstein.

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