Novel MAP Kinase Pathway Inhibitors to Treat Pancreatic Ductal AdenoCarcinoma

DESCRIPTIONprovided by applicantPatients diagnosed with advanced pancreatic ductal adenocarcinomaPDAChave ayear survival rate of less thanThese tumors have the highest reported incidence of KRAS mutations among all human cancersBecause of these observationsthere has been considerable interest in developing direct inhibitors of RAS mutants such as KRASHoweverattempts to directly inhibit KRAS have to date been unsuccessfulAn alternative approach is to target downstream effectors of KRAS on the MAPK pathwayExtracellular Regulated KinaseandERKare serine threonine protein kinases which are downstream components of the RAS RAF MEK signal transduction pathwayAberrant activation of ERK has been demonstrated in many human tumorsincluding pancreatic cancerERK inhibitors could prove very useful as therapies to treat tumors with RAS mutations such as PDACThis proposal aims to determine the potential of Kalyraandapos s novel ERK inhibitors as treatments for PDAC via the following aimsPhaseCharacterization of Novels Leads in Models of Pancreatic CancerAimEvaluatelead molecules in preliminary in vitro ADME and Plasma Protein Binding studiesAimConfirm efficacy oflead molecules vsa panel of human RAS mutant pancreatic cancer cell linesAimDetermine PK and in vivo efficacy of topleads in an in vivo model of KRAS pancreatic cancerPhase IIAdditional studies to enable selection of a Development CandidateAimCharacterize the effects of lead ERK inhibitors in combination studiesAimADME and Preliminary ToxicologyAimPharmcokinetics for Species Selection for Toxicology and Pilot ToxicologyAfter completion of the studies outlined in this proposalwe will have selected a drug candidateto enter IND enabling toxicology studies in support of filing an IND with the FDA to begin humanclinical trials for the development of a novel effective treatment for pancreatic ductaladenocarcinoma PUBLIC HEALTH RELEVANCEPancreatic ductal adenocarcinomaPDACis almost universally fatalThe annual number of deaths equals the number of newly diagnosed casesdespite maximal treatment with current standard of careKalyra is developing a novel orally bioavailable MAP kinase pathway inhibitorwith a new mechanism of actionKalyraandapos s novel inhibitors offer the potential to deliver best in class drugs for inhibiting the MAP Kinase pathway both in terms of efficacy and tolerabilityThese inhibitors offer the potential to effectively tret patients whose cancers are associated with activation of the MAP kinase pathwaywhich include those with PDACWith lead molecules in handthis proposal aims to conduct the non clinical studies required to select a development candidatewith the goal of developing a novelsafe and well tolerated therapy for the treatment of PDAC