Stromal targeting to improve the efficacy of systemically administered drugs for pancreatic ductal adenocarcinomas

Project Summary Only about 20% of pancreatic ductal adenocarcinoma (PDAC) patients are expected to survive one year from diagnosis, with the overall 5-year survival rate reported at a devastatingly low 8%, which is the lowest 5-year survival rate of all major cancers. A hallmark of PDAC is the dense extracellular stroma called the desmoplasia, which can occupy up to 90% of the tumor volume. The desmoplasia acts as a physical barrier preventing drugs from reaching the tumor cells. Additionally, the desmoplasia acts as a barrier that prevents immune cells from infiltrating the tumor, limiting the efficacy of immunotherapies. Systemically administered stromal targeting therapies have provided a promising route for reducing desmoplasia and allow both cells and drugs to enter the tumor more readily. However, these agents have a wide range of off-target effects, which limits the dose that the patient can receive. The overall goal of this proposal is to advance a local controlled release platform for intratumoral delivery of hyaluronidase, allowing for locally elevated concentrations of the enzyme without systemic involvement. Aim 1 will focus on the use of a multi-scale modeling approach to define the parameter space of implant design needed to achieve a uniform distribution of hyaluronidase within excised human tumors. Aim 2 is focused on the use of medical imaging to characterize the effects of stromal targeting agents on tumor blood flow and drug accumulation. Aim 3 will characterize the effects that stromal targeting therapies have as immunomodulatory agents for improved immune surveillance and evaluate treatment efficacy. The proposed studies will establish a novel approach for targeting tumor desmoplasia, improving mass transport into the tumors, and enhancing immune cell infiltration into the tumors.