Development of a Pharmacoprotector for Platinum Toxicities

Project Summary Abstract Reducing drug toxicity while enhancing efficacy represents a major goal of precision medicine In this SBIR Phase I application we propose a novel concept in drug therapy that is the development of a pharmacoprotector a small molecule that is co administered with a second drug to reduce its toxicity allowing it to be more safely and efficaciously used The overall goal of the proposed research is to discover and validate lead small molecule pharmacoprotectors which inhibit the organic cation transporter OCT a transporter highly expressed in tissues of toxicity for anti cancer platinum drugs In particular OCT is expressed in the kidney cochlea and basal ganglia cells of neurons A second goal is to obtain proof of concept data using a prescription drug ketoconazole which was identified as a potent and selective inhibitor of the organic cation transporter OCT OCT has recently been shown to be involved in the accumulation of two highly toxic anti cancer platinum drugs in various tissues i oxaliplatin accumulation in the nervous system leading to peripheral neuropathy and ii cisplatin accumulation in cochlear and renal epithelia leading to the ototoxicity and nephrotoxicity associated with the drug Two aims are proposed In Aim we will identify OCT specific small molecule inhibitors as lead pharmacoprotectors by screening a small chemical library of patentable drug like compounds enriched in compounds with the structural features of OCT inhibitors In Aim we will perform in vitro assays to test lead compounds identified in Aim for their abilities to reduce the toxicities and uptake of oxaliplatin and cisplatin in various cancer cell lines In addition we will evaluate the pharmacokinetics and tissue accumulation of oxaliplatin and cisplatin in mice with and without concomitant administration of ketoconazole Our methods and analyses for our studies will include high throughput screening assays using a fluorescent probe assay in OCT over expressing cell lines in vitro assays for cytotoxicity and platinum uptake analysis of plasma and tissue samples with ICP mass spectrometry to detect platinum pharmacokinetic analysis of plasma and tissue samples and The longterm goal of the proposed research is to develop FDA approved pharmacoprotectors that can be used in combination with oxaliplatin to modulate its dose limiting toxicity peripheral neuropathy and cisplatin to reduce both ototoxicity and nephrotoxicity Narrative Chemotherapeutic drugs used to treat cancer are among the most toxic of all prescription drugs This research project is aimed at developing a safe new drug that can be given together with highly toxic chemotherapeutic agents to reduce their toxicities The new drug would prevent accumulation of the chemotherapeutic drugs in body tissues associated with toxicity such as the kidney and the ear