TARGETING THERAPY OF HUMAN BREAST CANCER

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION: (Applicant's Description) Abnormalities in differentiation and growth control are common occurrences in human cancers. Treatment of human melanoma cells with the combination of recombinant human fibroblast interferon and the protein kinase C-activating, antileukemic compound mezerein results in a loss of tumorigenic potential that correlates with an irreversible suppression in proliferative ability and induction of terminal differentiation. It is hypothesized that this process is associated with differential expression of genes that may directly regulate cancer cell growth and differentiation. Through the use of subtraction hybridization, we have identified a gene associated with induction of irreversible growth arrest, cancer reversion and terminal differentiation in human melanoma cells, melanoma differentiation associated gene-7 (mda-7). Ectopic expression of mda-7 using a recombinant adenovirus, Ad.mda-7 S, results in growth suppression and apoptosis in diverse cancer cell types, including tumor cells with wild-type p53 or mutant for p53, Rb or p53 + Rb. Additionally, Ad.mda-7 S inhibits the growth and progression of human breast and cervical cancer cells in vivo in nude mice. In contrast to its effect on cancer cells, mda-7 displays no apparent negative effect on growth or survival in normal human skin fibroblast or mammary epithelial cells. In this context, mda-7 may prove useful for selectively targeting human breast cancer cells for eradication. Studies will be conducted to determine the effect of Ad.mda-7 S alone, and in combination with chemotherapy or radiation, on the in vitro and in vivo growth in nude mice of human breast cancers. Subtraction hybridization has also been used to clone a gene directly associated with cancer progression, progression elevated gene-3 (PEG-3). Genomic walking permitted the isolation of the promoter region of the PEG-3 gene, PEG-Prom. PEG-Prom-luciferase reporter constructs display high-levels of activity in human cancer cells, including breast cancer cells, and low or no activity in normal human cells. We propose to construct cancer inhibitory recombinant adenoviruses (CIRAs) utilizing the PEG-Prom to control expression of indicator genes [luciferase and green fluorescence protein (GFP)] and genes that induce growth suppression, apoptosis or toxicity [mda-7, wild-type p53 or the herpes simplex virus thymidine kinase gene (HSV-TK)]. These viruses will be used to determine if the PEG-Prom can specifically target the expression of genes to human breast carcinoma cells. If successful, this approach, termed CURE (cancer utilized reporter execution), could provide a novel means of therapy for human breast cancer without inducing nonspecific damage to normal tissues.