PROJECT SUMMARY Annually, pancreatic cancer (PC) has a global incidence of more than 495,000 cases and a mortality rate of almost 460,000 cases. Most of these patients (~80%) receive late-stage diagnoses when their tumors cannot be surgically resected, necessitating pharmacotherapy. A majority of PC patients (81%) have dense, fibrous stroma tissue surrounding their tumors, which is a negative prognostic. Despite treatment, PC has the lowest 5-year survival rate of all cancers. Nanomedicines have been developed for use in oncology to reduce toxicity and improve efficacy. Indeed, drugs like protein-bound paclitaxel nanomedicine (Nab-PTX, Abraxane) and liposomal irinotecan (Nal- IRI, Onivyde) have led to dramatic improvements in response rates for cancers such as breast, lun g, and leukemia. However, nanomedicines’ efficacy gains in PC have fallen far short of those seen in other indications. This stems in part from PC’s stromal tissue that blocks the extravasation and penetration of large nanomedicines like Nab-PTX and Nal-IRI (> 100nm). To overcome the delivery challenges of existing nanomedicines, Duo Oncology is developing DUO- 207, an ultrasmall nanoparticle (< 30 nm) comprised of a copolymer-conjugated gemcitabine (PGEM) that encapsulates paclitaxel (PTX). DUO-207’s fixed dose combination delivers the active moieties in GEM and Nab-PTX, a current standard of care (SoC) for advanced PC. DUO-207 contains four innovations that address gaps in this SoC therapy to optimize safety, efficacy, and convenience. 1) The patent-pending polymer chemistry behind PGEM protects GEM from rapid inactivation via cytidine deaminase in the blood and liver. Clinically, large doses of GEM are administered to compensate for rapid inactivation and increase the drug’s bioavailability to tumor tissue but this approach contributes to dose limiting toxicity. 2) In DUO-207, GEM is conjugated to the polymer, facilitating its controlled gradual release and providing prolonged exposure to GEM, which has been associated with improved clinical efficacy. 3) The bonds that link GEM to the polymer are sensitive to three conditions common to the tumor microenvironment, thereby aiding the release of GEM adjacent to cancer cells. 4) Lastly, our novel polymer chemistry allows for the self-assembly of 14nm PGEM micelles that can accommodate high drug loading of PTX in a single i.v. infusion. DUO-207’s ultrasmall size allows for its effective penetration of and accumulation in tumor tissue as demonstrated in our preclinical orthotopic model of PC using genetically engineered Kras-Pdx1-Cre (KPC) cells that produce dense stroma. In this application we propose to perform murine toxicology and tumor growth studies to build a safety and efficacy profile for DUO-207 compared to current Soc. Ultimately, the innovations of DUO-207 will improve survival outcomes, the toxicity profile, and quality of life for patients suffering from advanced PC.