Advancement of ACXT-3102 for the Treatment of Pancreatic Adenocarcinoma (PDAC)

Project Summary Abstract Pancreatic cancer is a devastating disease with a very lowyear survival rateTherapeutic options are limited in efficacy and many have substantial toxicityTargeted drug delivery may improve the therapeutic index of cancer drugs by enhancing drug localization to the cancer cell while minimizing off target side effectsreceptors are highly expressed in pancreatic and other cancers compared to healthy cellsAccuronix Therapeutics is developing ACXTa molecule with therapeutic potential licensed from Washington University School of Medicine in StLouisWUSMACXTis comprised of aligand covalently bound to the ferroptosis inducing molecule erastinPreliminary data show that ACXTincreased the cytotoxicity against pancreatic tumor cells in vitro byfold compared to erastin aloneACXThas tremendous potential as a novel treatment option for pancreatic and perhaps several other types of cancerA series of drug optimization strategies will be explored in an effort to improve the solubilityand delivery of an already viable cancer drugThe objective of these studies will be to enhance further the efficacy of ACXTFor this Phase I STTR projectAccuronix Therapeutics will work with researchers from WUSM to improve the bioactivity of its lead candidate ACXTThe primary endpoint is enhanced efficacy as measured by increased survival in murine models of pancreatic cancerWe will also asses for any off target drug effects including anemia and work to minimize these by clarifying the relationship between toxicity and dose scheduleThese improvement efforts will include formulation concepts commonly applied in the pharmaceutical industry to increase drug solubility in aqueous solutions ultimately leading to increases in bioavailability andmost importantlybioactivityThe most immediate change in relation to ACXTs current composition regards the generation of seven additional salt variantsThese then will be tested using alternative vehicle compositions to enhance drug half lifeFinallythe best performing salt formulation will be evaluated employing detailed biodistributionPK PDand efficacy studies in mice via the parenteralIVand oralPOadministration routes to determine the best method of deliveryAt conclusion of this Phase I STTR grantwe will have demonstrated the utility of ACXTin pancreas cancer treatmentjustifying advanced studies toward clinical translation for the benefit of patients suffering from pancreatic adenocarcinoma Project Narrative The primary goal of this Phase I STTR application is to develop ACXTinto an improved therapeutic for the treatment of pancreatic adenocarcinomaTargeted cancer drugs hold great promise to increase therapeutic indices while minimizing putative off site side effectsImprovements will be accomplished bygenerating alternative salt variants to address aqueous solubilityexploring alternative vehicle compositions to enhance drug half life andperforming detailed biodistributionPK PDand efficacy studies in mice via the parenteralIVand oralPOadministration routes to determine the best method of delivery