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Development of a Pharmacoprotector for Platinum Toxicities

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43CA206705-01A1
Agency Tracking Number: R43CA206705
Amount: $225,000.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: 102
Solicitation Number: PA16-302
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-05-17
Award End Date (Contract End Date): 2019-11-30
Small Business Information
Atherton, CA 94027-3017
United States
DUNS: 078401096
HUBZone Owned: No
Woman Owned: Yes
Socially and Economically Disadvantaged: No
Principal Investigator
 (650) 361-1192
Business Contact
Phone: (650) 361-1192
Research Institution

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

* Information listed above is at the time of submission. *

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