HIGHLY INNOVATED TARGETED THERAPY OF MELANOMA

Despite the recent development of novel therapeutic approaches no curative treatment is available for advanced stage melanoma with year survival below Targeted therapy is one of the most promising therapeutic strategies to the treatment of cancer and is a key component of precision medicine which aims to individualize cancer treatment for a given patient IL RA an oncogenic isoform of the ubiquitous IL RA receptor is overexpressed in primary and metastatic melanomas but not in normal tissue This receptor has been underutilized therapeutically partly due to the lack of clinically applicable translational tools Recently a novel class of unique ligands has been developed that not only selectively bind the IL RA receptor but also after internalization reach the desired cellular compartment including the nucleus Specifically we hypothesize that our patented DNA binding agent showing nanomolar potency IC nM or lower against melanoma cells but not normal cells no effect at nM when conjugated to IL RA specific ligands capable of delivering a payload to the nucleus or cytoplasm of melanoma tumor cells will generate a new class of highly efficacious melanoma selective therapeutic agents with great translational and commercial potential We propose two specific aims Aim To develop ligand drug conjugates targeting melanoma tumors expressing the IL RA receptor Two conjugation strategies will be employed delivering either a stable drug conjugate containing domains critical for nuclear delivery of the payload or a pH sensitive linker that liberates drug from the internalized conjugates in the lumen of endocytic vesicles to the cytosol and other organs Aim To assess in vitro and in vivo efficacy of the conjugates in melanoma models with variable expression of IL RA We will test and compare the efficacy of synthesized conjugates in vitro and in vivo models using cells tumors with both high and low expression of the IL RA receptor In summary we propose to develop a new unique and highly promising targeted therapy both conceptually and practically for melanoma patients This concept has a double advantage as it combines selectively binding melanoma cells ligands with a melanoma specific highly cytotoxic DNA binding agent This double advantage approach will explore ligands that not only bind to the IL RA receptor on melanoma but are internalized to deliver a cytotoxic payload to the desired cellular compartment This further increases the chances of developing safe and efficacious targeted therapeutics with increased potency and selectivity The results of these innovative studies will deliver the required proof of principle and will support the Phase SBIR grant application for advanced preclinical development aimed at the initiation of clinical studies in humans and the subsequent commercialization of validated conjugate Project Narrative Our proposal addresses the critical unmet needs of melanoma patients especially those with advanced stage disease We propose to develop a new unique and highly promising targeted therapy for melanoma patients