Sunday, May 11, 2025
5/11/2025
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, OCT2, a transporter highly expressed in tissues of toxicity for anti-cancer platinum drugs. In particular, OCT2 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 2, OCT2. OCT2 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 1, we will identify OCT2 specific small molecule inhibitors as lead “pharmacoprotectors” by screening a small chemical library of 30,000 patentable drug-like compounds enriched in compounds with the structural features of OCT2 inhibitors. In Aim 2, we will perform in vitro assays to test lead compounds identified in Aim 1 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 OCT2 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.
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