Translational Development of a Targeted and Stroma-breaking Nanoparticle Drug for Pancreatic Cancer Therapy

Project Summary Resistance to therapy is the major clinical challenge in pancreatic cancer therapyLow efficiency in drug delivery and aggressive tumor biology are the major causes of a poor therapeutic responseIt is well known that the presence of a dense fibrous tumor stroma creates a drug delivery barrier and promotes aggressive biology and drug resistance in pancreatic cancer cellsThe objective of our translational research project is to develop a new generation of receptor targeted and protease active targeting ligand and stroma breaking nanoparticle drug delivery platform for effective treatment of advanced pancreatic cancerOur extensive research led to the development of a new tumor targeting approach using a recombinant uPAR targeting ligand containing the amino terminal fragmentATFof uPA fused with the catalytic domain of matrix metalloproteinaseATFmmpNovel designs of ATFmmpligand not only ensure enhanced intratumoral delivery of therapeutic agentsbut also enable breaking tumor stroma cellular and extracellular matrix barriersWe also developed a biodegradable hyaluronic acid nanoparticle carrying an active metabolite of irinotecanSNHANP SNOur results demonstrated that ATFmmpconjugated HANP SNsignificantly enhanced drug delivery to tumors in KRAS driven transgenic mouse and human pancreatic PDX tumor modelsImportantlythe nanoparticle drug migrated out of tumor stroma and penetrated through the basement membrane lining ductal cancer cells to enter tumor cellsAs a resultsystemic delivery of ATFmmpHANP SNsignificantly inhibited tumor growthIn comparison with current combination therapiesFOLFRINOX or gemcitabine Nab PaclitaxelATFmmpHANP SNtreatment significantly prolonged survival in the PDX tumor models derived from drug resistant pancreatic cancer patientsTo translate this novel approach for target therapy in cancer patientsin this phasestudywe will develop a new generation of tagless human ATFmmpligands that are optimized for the GMP production and have high binding affinitytarget specificity and MMPenzymatic activityThe proposed studies in Aimwill engineer a stable ATFmmpRexpressing CHO cell line and a Bsubtilis secretable protein expression system for large scale production of tagless ATFmmpRWe will then evaluate and compare their production procedureprotein yieldtarget specificityand MMPactivity in vitro and in vivo to select the most suitable targeting ligand for drug developmentAimFinallytherapeutic effect of ATFmmpRwill be determined in a pancreatic PDX tumor modelAimThe milestones of this phase I research project areto develop ATFmmpHANP Ras a stroma breaking and targeted nanoparticle drug delivery platform for future commercializationandto develop a targeted nanoparticle drugATFmmpRHANP SNfor the Phase II study aimed at the Investigational New DrugINDenabling preclinical studies for the translational development of ATFmmpHANP SNfor targeted therapy of advanced pancreatic cancer Project Narrative Dense tumor stroma that consists of inflamed normal cells and extracellular matrix in pancreatic cancer creates a drug delivery barrier and promotes aggressive biology and drug resistance in pancreatic cancer cellswhich attributes to a poor therapy response of pancreatic cancerThe proposed Phaseresearch project will develop a new generation of tumor targeted and stroma breaking recombinant protein ligand and a novel drug delivery platform for future commercializationThis novel targeting ligand will then to be used develop a receptor targeted and stroma breaking hyaluronic acid nanoparticleHANPdrug for conducting translational preclinical studies in the SBIR Phase II research project aimed at the development of a clinical trial in advanced pancreatic cancer patients