Common use of SCIENTIFIC BACKGROUND Clause in Contracts

SCIENTIFIC BACKGROUND. Base-excision repair (BER) is a key resistance mechanism employed by cancer cells to survive chemotherapy-induced DNA damage, and inhibiting BER improves the therapeutic index of these agents in preclinical models. TRC102 (methoxyamine hydrochloride) is an inhibitor of BER with a unique mechanism of action. TRC102 exerts its effect by rapidly and covalently binding to chemotherapy-induced apurinic/apyrimidinic (AP) sites generated by glycosylase removal of abnormal bases. TRC102-bound DNA is no longer a substrate for BER enzymes and is instead irreversibly cleaved by topoisomerase II resulting in double-strand DNA breaks that trigger cellular apoptosis. The induction of apoptosis by TRC102 is selective for cancer cells because they express high levels of topoisomerase II. In normal cells with low topoisomerase II expression, TRC102-bound DNA is predominantly excised and replaced with normal DNA by the long patch DNA repair system. The efficacy of TRC102 is independent of tumor O-6-methylguanine-DNA methyltransferase (MGMT) expression, mismatch repair status, or p53 status. TRC102 is synergistic with a wide variety of cancer therapies including antimetabolites, oxidizing agents, alkylating agents, and poly ADP ribose polymerase (PARP) inhibitors. The active molecule is a small organic amine that is highly water soluble and nearly completely bioavailable after oral administration.