Genomics Strategies in Drug Discovery for Cancer Prevention
Over the past several decades, strategies for the discovery of new pharmacologic agents have progressed from being purely empirical to target-based. Although empirical approaches to drug discovery are still used, strategies based on our understanding of the molecular mechanisms of disease have become increasingly important platforms for the discovery of novel therapeutics. Through the development of a better understanding of the molecular biology of a disease target, scientists may identify biochemical or molecular pathways that are critical to disease induction and/or progression. Development of small molecules or biological agents that can modulate such pathways may provide effective, target-specific approaches to disease prevention and/or therapy.
As part of our program in drug discovery and development for cancer chemoprevention, a team of scientists led by David L. McCormick, Ph.D., D.A.B.T., Senior Vice-President and Director of IITRI, is using both genome-wide and gene-specific strategies to identify biochemical and molecular pathways that may serve as useful targets for chemopreventive drug design. In work presented earlier this year at the annual meeting of the American Association for Cancer Research, genomics strategies were used to identify genes and molecular pathways that are differentially expressed in experimental prostate cancers versus normal prostate tissue. The hypothesis underlying this work is that modulation of pathways that are dysregulated in prostate malignancies may provide an effective approach to disease prevention. Similarly, using an experimental model of oral cancer, we have compared expression patterns of specific genes in normal and neoplastic tissues to identify changes in gene expression that are associated with development of oral malignancies. The overall goals of these parallel programs are to identify pathways that may provide suitable targets for the design of chemopreventive drugs.
Genomics Approaches to Chemoprevention of Prostate Cancer
Canonical pathway analysis of genome-wide screening of normal and neoplastic prostate tissues identified integrin signaling as the pathway that was most frequently dysregulated in prostate cancers. These results suggest that pathways associated with integrin signaling may provide useful targets for the design of drugs for prostate cancer chemoprevention.
Studies of the expression of specific genes in prostate cancers identified cyclin D1, β-catenin, cellular retinoic acid binding protein 2 (CRABP2), peroxisome proliferator-activated receptor γ (PPARγ), retinoic acid receptor α (RARα), n-cadherin, and TCF4 as significantly up-regulated in prostate cancers versus normal prostate tissues. Conversely, androgen receptor, PPARα, RARβ, and retinoid "X" receptor γ (RXRγ) were significantly down-regulated in prostate cancers. Expression of RXRα and RXRβ were similar in normal and neoplastic prostate tissues.
The up-regulation of β-catenin and TCF4 in prostate cancers suggests that carcinogenesis in this site may be inhibited by modulation of Wnt signaling. Similarly, modulation of PPARγ action using agents such as indoles or thiazolidinediones may provide a useful approach to prostate cancer chemoprevention.
The observed differential expression of nuclear retinoid receptors (up-regulation of RARα, but not RXRα and RXRβ) suggests that ligands for RARα, but not RXRα or RXRβ, may be effective inhibitors of prostate carcinogenesis. This hypothesis is substantiated by the positive results of a prostate cancer chemoprevention bioassay of 13-cis-retinoic acid (a RAR agonist) and the negative results of a prostate cancer chemoprevention bioassay of bexarotene (a specific RXR agonist) in the Wistar-Unilever rat. These data suggest that differences in gene expression can provide a rational mechanism to identify possibly suitable targets for chemopreventive drug design.
Genetic Approaches to Chemoprevention of Oral Cancer
Working with colleagues from the Division of Cancer Prevention at the National Cancer Institute, IITRI scientists have also used gene-specific strategies to identify possible molecular targets for cancer prevention in several tissues. In recent work using an experimental model for oral cancer, IITRI scientists found that cyclooxygenase-2 (COX-2) expression in oral cancers was increased by 8- to more than 70-fold in comparison to normal oral tissue. These data suggested that inhibition of COX-2 activity may provide a useful approach to the prevention of oral cancer.
In two follow-up studies, we demonstrated that oral carcinogenesis can indeed be inhibited by administration of non-toxic levels of either (a) a specific COX-2 inhibitor (celecoxib), or (b) a non-specific inhibitor of both the COX-1 and COX-2 isozymes of cyclooxygenase (piroxicam). The results of these studies in a model for oral cancer support our findings in the prostate cancer model system, and suggest that analysis of differential gene expression in normal versus neoplastic tissues may provide a useful, target-specific approach to the design of cancer preventive drugs.