Research in prostate cancer has been hampered by the lack of applicable animal models that reflect both the clinical and biologic behavior of human prostate cancer,in particular its metastatic potential. With genomic information available for human and animal models it may be possible to develop new models that match the clinical and biologic phenotype. Technologies are now available that allow the transfer of portions of the genome ranging from whole or partial chromosomes (consomic or congenic animals) to individual genes (producing animals by transgenicor homologous recombination technologies). What these technologies need are the defined genomic regions that characterize the clinical and pathologic basis of prostate cancer. The starting point would include a model of hormonally modulated tumors that spontaneously develop with age and which metastasize. The Lobund-Wistar rat is the only example of spontaneous metastasizing androgen-modulated neoplasia and will be used to initiate the development of a better model. We are encouraged that this may be possible; because of a preliminary genome sharing analysis suggest that the chromosoaml regiona involved in the Lobund-Wistar rat are syntenic to regions involved in human prostate cancer. Thus the Lobund-Wistar rat has features that match the clinical and potentially the genomic basis of human prostate cancer. By defining the genetic region(s) associated with the features common to human prostate cancer we propose to create susceptibility regions, that by virtue of comparative mapping could be used in either mouse or rat systems to engineer better animal models of human prostate cancer. Here we propose the studies necessary to validate and extend the identified chromosomal regions through genetic crosses. In addition, in order to shorten the interval to phenotypic evaluation we propose to develop a better phenotypic biomarker for early disease. The use of global gene expression patterns as an intermediate biomarker for subsequent tumor formation and metastasis would provide a unique fingerprint that could be evaluated in younger animals, thereby reducing the time to phenotypic analysis. We will develop an expression fingerprint that correlates with tumor formation using expression microarray technology and utilize this pattern as a phenotype in future evaluation of Lobund-Wistar rats. These studies are essential in the development of new animal models of prostate cancer.
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