Designing a 3D In Vitro Drug Screening Platform to Target the Interplay Between a Hypoxic and Activated Stromal Microenvironment for Pancreatic Ductal Adenocarcinoma
Wu, Nila (1), Sze, Daphne (4), D'Arcangelo, Elisa (1), Koritzinsky, Marianne (3), McGuigan, Alison (1, 2)
(1) Institute of Biomaterials and Biomedical Engineering, University of Toronto
(2) Department of Chemical Engineering & Applied Chemistry, University of Toronto
(3) Princess Margaret Cancer Centre, University Health Network, Toronto
(4) Faculty of Applied Science & Engineering, University of Toronto
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stroma produced by pancreatic cancer-associated fibroblasts (CAFs) resulting in stiffened tumour tissue, increased hydrostatic pressure within the tumour, and poor tumour tissue vascularization. The combination of these factors establishes a stromal barrier against chemotherapeutic drugs thus reducing their efficacy. Crosstalk between cancer cells and CAFs within the stroma, combined with the altered extracellular matrix, generates a hypoxic tumour core. In such low-oxygen environments, hypoxic tumour cells survive radiotherapy due to the absence of the oxygen enhancement effect necessary to achieve permanent DNA damage, consequently limiting the impact of radiotherapy for PDAC.
The potential for increasing radio-sensitivity by alleviating tumour hypoxia has been recognized, and FDA-approved drugs, such as the anti-diabetic drug metformin and the anti-malarial drug atovaquone have been redirected for this purpose; the latter identified in a 2D normoxic monoculture screen. These drugs demonstrated a reduction in oxygen consumption rate and tumour hypoxia in various cancer cell lines, however there was a limited effect observed in PDAC, possibly due to the unique stromal properties of this type of cancer.
Here we propose to conduct a drug screen for PDAC to specifically target the relationship between cancer cells, CAFs, and hypoxia. This project will design a 3D in vitro screening platform to identify drugs that target the interplay between cancer cells and CAFs in a hypoxic microenvironment reflective of the core tissue in PDAC to reduce local hypoxia and increase radiation sensitivity. The specific aims are: (1) to develop a high-throughput, disease-relevant in vitro co-culture platform (2) identify compounds that target PDAC tumour hypoxia (3) validate hits within a contextual PDAC microenvironment. The combination of a drug targeting relevant cell-microenvironment interactions and localized radiation dosing could be the needed therapy to improve pancreatic cancer patient survival rates.