This application is submitted in response to Notice Number NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Despite notable achievements in its treatment over the past two decades, cancer remains a challenging twenty-first century epidemic demanding new, more effective drugs. We have previously shown that nitric oxide (NO) induces differentiation and apoptosis in acute myeloid leukemia (AML). Glutathione S -transferases (GST) are involved in multi-drug resistance and are upregulated in cancer cell isolates. We have designed a class of diazeniumdiolate prodrugs that release NO upon interaction with glutathione in a reaction catalyzed by GST. Screening a library of these compounds with extensive lead optimization has led to the identification of O2-(2,4-Dinitrophenyl) 1 -[(4-ethoxycarbonyl)piperazin -1-yl]diazen-1-ium-1,2-diolate or JS-K as the most active compound of this class. JS -K has shown potent and broad anti-cancer activity in vitro and in vivo in multiple laboratories. JS-K has challenging solubility properties and in vivo stability properties. To further its advancement to the clinic, we have developed a unique P123 Pluronic(r) micellar JS-K formulation which solves these problems with its potential clinical use. With funding from R01 CA129611 we are refining this micellar formulation and are continuing to study the pharmacology and in vivo efficacy of Pluronic(r) micellar JS-K in xenograft tumor models. To speed clinical development we now submit this Competitive Revision Application to R01 CA129611. The goal of this application is to bring Pluronic(r) micellar JS -K to therapeutic human trials. Our hypothesis is that Pluronic(r) micellar JS-K is a highly effective and relatively non-toxic therapy for multiple cancers. This Competitive Revision Application will make possible progression to an Investigational New Drug (IND) application for Phase I human safety trials.
In Aim 1, we will perform synthesis of 1 kg JS-K Active Pharmaceutical Ingredient (API) compliant with Good Manufacturing Practices (cGMP). This work will be done by Richman Chemical, Inc., (www.richmanchemical.com/), a well -respected cGMP contract manufacturer pharmaceutical grade therapeutic compounds.
In Aim 2 we will formulate JS-K and Pluronic(r) P123 polymers into sterile unit dose vials using cGMP methods, and initiate a formal program to validate vial stability. This work will be done with Pyramid Laboratories, Inc. (http://pyramidlabs.com), an experienced contract pharmaceutical formulator.
In Aim 3 we will perform standard acute and 28-day pre-clinical toxicology studies in two species (rats and Beagle dogs) using Good Laboratory Practice (GLP) procedures. This work will be performed by the Preclinical Drug Evaluation Facility within the University of Utah School of Pharmacy. Finally, in Aim 4, with the assistance of Dr. Thomas Kennedy, a Utah faculty member who has previously authored successful applications, we will summarize the work accomplished in this Competitive Revision Application, and submit it as part of an IND to perform at the Huntsman Cancer Hospital initial human Phase I safety trials of P123 Pluronic(r) micellar JS -K as an exciting new therapeutic agent for cancer.
There is a great need for new drugs to treat Cancer. Work done in this project will develop a new drug called JS-K for the treatment of Cancer.
