Development of a protein drug for pancreatic cancer treatment

Abstract Pancreatic cancers are devastating diseases with five year survival rate less thanCurrentlythere is no effective treatment for advanced diseaseOne major barrier to efficacy of anti tumor therapeutics is the dense desmoplastic stromal responseEvidence suggests that cancer associated pancreatic stellate cellsCAPaSCproduce the stromal collagenThe ECM laid down by CAPaSC is considered to be one of the major contributors of resistance to established therapies of the diseasesDepleting CAPaSC and altering vessel density could significantly improve efficacy of existing pancreatic ductal adenocarcinomaPDACtreatmentsHowevercurrentlythere are no approved therapies that are able to deplete CAPaSCs in PDACWe have developed a novel therapeutic proteinProAgiousing rational protein designProAgio is designed to target integrinvat a novel sitenot the ligand binding siteProAgio specifically induces apoptosis of integrinvexpressing cells with high efficacy by a novel mechanism of drug actionrecruiting andampactivating caspaseat cytoplasmic domain ofWe reasoned thatsince both CAPaSC and angiogenic endothelial cells express high levels of integrinvand since ProAgio is very effective in inducing apoptosis of integrinvexpressing cellsProAgio should both deplete CAPaSC and eliminate new blood vessels in and around pancreatic tumorsThis unique strategy may prove advantageous in treatment of PDACOur STTR phase I studies demonstrated efficacy of ProAgio potentially as a PDAC treatment via various cancer modelsThe studies support our hypothesis that ProAgio can provide treatment benefit by simultaneously depleting the collagen producing CAPaSCs that support tumor desmoplasia and cancer cell growthwhile also eliminating newly grown cancer associated blood vessels that feed cancer cells and enable cancer metastasisData from our STTR phase I studies provides proof of principle for future clinical testsTo facilitate future clinical studies of ProAgio in PDAC patientswe propose toAimanalyze the pre clinical toxicologyTOXand pharmacokineticsPKof ProAgio with rats and monkeyTOX PK studies will enable IND application with US Food and Drug AdministrationFDAAimDetermine whether ProAgio can synergistically enhance treatment efficacy and delivery of immune checkpoint blockadesThis study will explore new therapeutic avenue for PDAC patients This research project develops and tests a novel protein agent for pancreatic cancer treatment