(99c) Re-engineering the tumor microenvironment to enhance efficacy of molecular and immune therapies in metastatic cancer

Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal disease with the lowest 1-year and 5-year survival rates of any cancer. This is due, in part, to the extremely metastatic behavior of pancreas carcinoma cells and their extreme resistance to both chemical and radiotherapies. Importantly, we now know that a strong, but nevertheless unique, fibroinflammatory, or desmoplastic, response is present in the tumor microenvironments of PDA. Indeed, these features generate ‘stromal resistance’ through physical barriers to effective treatment that include inordinately high interstitial fluid pressures, elevated tumor microenvironment stiffnesses, vascular collapse and low permeability; essentially creating a drug-free sanctuaries in PDA by critically limiting the delivery, diffusion, and convection of small molecule and immune therapeutics. To overcome these barriers, we develop strategies, that are informed by our work to define the fundamental physical behavior of solid tumors, to re-engineer the tumor stroma to normalize disease and enhance efficacy of therapeutic interventions. Indeed we have recently defined free and immobilized fluid phases within tumors and extracellular matrix components that drive elevated tumor pressures and hinder small molecule diffusion. By targeting these drivers of stromal resistance in the tumor, pressures are normalized, vascular patency is restored following re-expansion of microvasculature, and enhanced drug delivery and distribution results throughout the tumor mass from improved diffusion and convection. In the context of concomitant cytotoxic chemotherapy tumor volume is decreased and metastatic burden and overall survival can be significantly improved.