Targeting LIF/LIFR in pancreatic cancer

ABSTRACT Pancreatic cancerPCwill be the second leading cause of cancer related mortalities byhighlighting the importance of the development of new therapeutic modalitiesOne of the important reason of the PC aggressiveness is the presence of dense stromapredominantly consisting of activated fibroblast and extracellular matrixECMproteinsThe deposition of the ECM proteins constricts the blood vessels leading to poor tumor perfusionwhich impede the delivery of chemotherapeutics like gemcitabineresulting in the poor therapeutic efficacyMultiple studies have attempted to target PC stroma by modulating TGF betaEGFRand hedgehog signaling and enzymatic degradation of the ECM protein in the preclinical modelsbut with little successUsing our novelD organoid systemgenerated from the PC and stromal cellswe investigated the impact of a novel firstinclass inhibitor of leukemia inhibitory factor receptorLIFRECInternational patent WOAon specific targeting of the activated fibroblast associated with the PCECis a novel steroidal small molecule that can readily diffused in microenvironment and specifically targets stromal cells by inhibiting leukemia inhibitory factorLIFinduced ECM expression and remodeling through JAK STAT pathwayLIF is overexpressed in a subset of tumors that undergo extensive matrix remodelingand have high stromal compartment such as PCOur preliminary studies in autochthonous murine models have demonstrated that LIF is significantly upregulated during PC progressionTargeting LIF will offer another advantageby depleting cancer stem cellsit will further prevent the therapeutic resistanceBased on previous findings and our preliminary studieswe hypothesize that LIFR targeting by ECwill reduce the desmoplastic reaction in pancreatic tumor and improve the efficacy of the gemcitabine treatmentThis fast track application will evaluate the in vivo efficacy of ECin combination with gemcitabine using state of art autochthonous murine modelspatient derived xenograftsPDXand metastatic models during Phaseand Phasestudies based on measureable milestonesIn Phase Iwe will evaluate the impact of ECand gemcitabine combination on pancreatic ductal adenocarcinomaPDACtumorigenesis using orthotopicOTmurine modelsThe proposed study will transition to the phaseafter significant clinical benefit in terms of tumor regressionminimumby the combination therapyIn Phasewe will undertake Aimto determine the therapeutic efficacy of ECtreatment in combination with gemcitabine in autochthonous and PDX models of PDAC modelAimwill determine the therapeutic efficacy of ECtreatment in combination with gemcitabine in metastatic models of PDACand in Aimwe will proceed with process development and GMPgood manufacturing practicesynthesis of ECfor dose ranging toxicology studies in rodents and dogsIMPACTSimultaneous targeting of the pancreatic tumor stroma and stemness by ECattributes responsible for inherent drug resistancewill provide novel therapeutic regimen for the management PC patientsWith the availability of GMP grade ECthe findings from the proposed study will quickly lead to the clinical trials PROJECT NARRATIVE Pancreatic cancer has one of the worst prognoses of all cancers due to intense stroma that impedes the perfusion of chemotherapeutics and impact therapy resistance to the cancer cellsThe proposed research seeks to evaluate the therapeutic potential of small steroidal molecule ECin combination with gemcitabine that will simultaneously target pancreatic tumor stroma and cancer cellsThe knowledge thus gained will provide a novel therapeutic regimen for the cure and management of pancreatic cancer patients