The Pancreatic ductal adenocarcinoma (PDAC), mostly a mutant K-Ras driven, in which hypoxia triggers acidification of extracellular matrix, epithelial-to-mesenchymal transition (EMT)/cancer stemness (CSCs), metastasis, desmoplasia, and chemoresistance. These pathological changes grim the prognosis of the disease. Thus, EMT/CSCs and desmoplasia must be destructed to improve the prognosis. Emerging evidence indicates that these processes are disrupted by targeting the extracellular signal-regulated kinases (ERKs) downstream of the mutant K-Ras-signaling pathway. However, in the clinic, the weak bioavailability and dose-limiting toxicity reduce ERK inhibitors' efficiency in halting tumor progression. Thus, there is a critical need to develop drug carriers that selectively target PDAC tissues and suppress the growth of cancer cells via sustained drug release deep into the tumor. We recently discovered that the efficacy of SCH 772984, an ERK-inhibitor (ERKi), can be enhanced in systemic delivery if we encapsulated the ERKi in a pH/hypoxic-responsive nanocarrier (pHNPs) attached with a tumor-penetrating peptide iRGD. Our preliminary studies suggest that ERKi suppresses the production of CSCs and desmoplastic regulator protein CTGF/CCN2 in pancreatic cancer cells via blocking AP- 1-signaling. Finally, we also found that CTGF blockade by ERKi may participate in tumor fibroblast cell activation, a hallmark of desmoplastic reaction. Building on these exciting preliminary findings, we propose finding the optimal variant of ERKi-pHNPs, unraveling the mechanisms of response to ERKi therapy in human and murine PDAC cell lines, and therapeutic efficacy alone or combined with gemcitabine and/or Nap-paclitaxel using genetically engineered mouse models (GEMM) and Patient-derived xenograft (PDX) mouse models. The goal of the project is to submit an investigational new drug application (IND) to the FDA with the long-term goal is to translate this novel therapeutic product to the clinic to treat Veterans. We propose three Aims. In Aim 1, we will synthesize different ERKi-pHNPs variants by modifying the moieties, identifying an optimal variant from them by determining the in vitro and in vivo functional efficacy, and evaluating the mechanism of action through the in vitro characterization in PDAC cells. In Aim 2, we will determine the MTD, toxicity, and pharmacokinetics (PK) of an optimal variant of ERKi-PHNPs in the presence or absence of chemotherapy in tumor-bearing CDX mice. Finally, in Aim 3, we will evaluate the effect of optimal ERKi- pHNPs and free-GEM in translational studies using KPC and patient-derived tumor xenograft (PDX) models for PC. The effect of Nab-paclitaxel with these combinations will also be tested. To realize these aims, we have developed stimuli-responsive polymers (Mol. Pharmaceutics 2021, 18, 87−100 ), a unique in vitro desmoplastic model (Mol Cancer Ther; 18, 2019), standardized non-invasive, high-resolution imaging, and high-thorough put...