622. Discovery of Targeting Peptides for Selective Therapy of Medullary Thyroid Carcinoma

Abstract

Adenovirus efficiently infects a broad range of target cells, thereby preventing selective gene transfer. Moreover, several cell types and tissues including primary tumors are refractory to adenoviral infection, mainly because of low expression levels of coxsackie-adenovirus receptor (CAR). Thus, identification of cancer selective ligands which yield gene transfer to neoplastic cells by minimizing transduction of normal cells is a key issue for successful cancer therapy. We initially analyzed adenoviral receptor expression in human medullary thyroid carcinoma (MTC) cells and found significant differences in CAR and av integrin protein levels between MTC-derived TT cells in vitro and established xenograft tumors in mice, indicating a lack of av integrin expression on growing tumors. We isolated MTC cell-specific peptides by biopanning a phage display library on cultured cancer cells and on tumors in vivo. Candidates were selected by performing two–three rounds of subtraction. Selected phages showed 5 to 22-fold higher binding efficiency for TT cells when compared to wild-type M13 phage or other human cell lines in vitro and in vivo in a RET transgenic mouse model. Importantly, the best binding peptide mediated efficient internalization of the phage, indicating that the identified ligand should be suitable to improve selectivity of adenoviral gene transfer to medullary thyroid tumors in vivo.