Development of Novel Targeted Chemotherapeutics for the Treatment ofMalignant Pleural Mesothelioma

Abstract Malignant Pleural MesotheliomaMPMis an aggressive cancer effecting the lining of the lungs and is most often caused by exposure to asbestosMPM is difficult to detect and is typically diagnosed late resulting in a median survival of just one year and ayear median survival of onlyPemetrexedPmxis the standard of care but quality of life is poor due to Pmx toxicitiesThe purpose of this Direct to Phase II SBIR grant application is to examine several novel therapeutic molecules as a treatment for patients with MPMThese molecules are unique as they are designed to be small molecule targeted therapeuticsThese FTACfacilitative transporter anti cancermoleculesAGF seriesare potent chemotherapeutics which kill cells by inhibiting GARFTaseglycinamide ribonucleotide formyltransferasewhich inhibits purine synthesis and results in cell deathBut what differentiates FTAC molecules and makes them uniquely effectiveis that FTAC molecules exhibit selective uptake by the PCFTproton coupled facilitative transporterThe PCFT is a scavenger system that only exists in cancer cells and thereby offers a mechanism to differentiate a cancer cell from a normal healthy cell for a targeted therapeutics approachInitial studies have shown FTAC molecules to befold more selective to cancer cells when compared to standard of careSOCchemotherapeutics and comparable or superior in cytotoxicity in early animal studiesAs the testing of our FTAC molecules is in its infancy but with very exciting and promising resultswe plan to thoroughly examine several FTAC molecules to identify those compounds that show maximal selectivity and efficacy with minimal side effectsMPM was chosen as the initial disease to study as it has very few effective therapeutic treatment options for patients and MPM tissues express high levels of PCFTwhich should increase FTAC s targeting efficiency and produce a superior therapeutic with fewer negative side effectsIn order to achieve this goalthe following Specific Aims are proposedAimSynthesize and test analogs of AGFfor improved potency and PCFT selectivityAimTesting of compounds for potency and PCFT selectivity in vitro and in vivoAimTesting the efficacy of up tocompounds in MPM PDX SCID mice modelsAimInitiation of IND enabling safety and DMPK studies on the top compounds for clinical development To the best of our knowledgethese molecules are the first cytotoxic compounds with selective uptake and therefore have the potential to provide a significant clinical benefit to MPM patients