Pleiotrophin (PAIN) is a cytokine that promotes growth and development. Inappropriate expression of PTN has been shown to result in tumorigenicity which suggests that inhibiting this pathway may be useful chemotherapeutically.
The specific aim of this application is to demonstrate the feasibility of developing a reporter assay for the PTN signaling pathway with a long-term objective of using the assay to discover drug leads for the treatment of cancers induced by pleiotrophin overexpression. The appropriate components of the putative pleiotrophin pathway include the receptor protein tyrosine phosphatase (RPTP) beta/zeta, beta-catenin and members of the Tcf/Lef family of transcription factors. A reporter plasmid will be constructed that consists of a Tef/Lef minimal binding motif driving a green fluorescent protein. The construct will be transfected into MDA-MB-231 and NIH 3T3 cell lines and stable transformants will be isolated. Confirmation that the reporter system reflects the activity of pleiotrophin will be tested and confirmed with a series of positive and negative controls. The assay will be used to screen a small molecule library and PTN peptide fragments to identify first generation inhibitors of PTN signaling and the minimal core PTN peptide antagonist.
Pleiotrophin (PTN) is a cytokine that promotes growth and angiogenesis and its overexpression can lead to tumor growth. The development of a reporter assay based on a novel PTN/receptor phosphatase signaling pathway will serve as a new drug discovery tool at Oridigm Corp. It will be useful in the search for antiproliferative drugs involving a relatively large number of cancers that overexpress PTN such as glioblastoma, prostate, lung, and breast cancers. Compounds discovered will be developed as human cancer therapeutics.
