Metastasis of tumor cells is a key process in the progression of cancer. This process is tightly regulated by a small number of proteins essential to the intravasion of tumor tissue and subsequent neovascularization of the tumor, and additionally the invasion of non-cancerous tissue by tumor cells shed from the parent body. Up regulation of the expression of uPAR has been shown to significantly contribute to these processes. Conversely, antisense mediated down regulation of uPAR significantly inhibits both neovascularization and invasion by metastatic cells. Previous results show that the expression of uPAR is post-transcriptionally regulated through an undefined mechanism involving uncharacterized proteins interacting with two distinct regions of the mRNA uPAR. This grant will find and characterize peptide mimetics of the endogenous binding proteins, as a prelude to establishing a high throughput screening program to identify small molecules drugs capable of modulating this regulatory process. Structurally defined peptide libraries will be constructed on polystyrene beads employing a mix and split protocol. A solid phase screening process will be employed to find peptide mimetics, which will subsequently be characterized in the solution phase.
Identification of peptide mimetics of the endogenous uPAR mRNA binding proteins will allow for the development of a high throughput screening program to identify a new class of anti-cancer drugs which elicit their effects through a novel post-transcriptional mechanism.
