Development and evaluation of a loco-regional drug delivery system for the treatment of pancreatic cancer
Dr H Kelly
Dr C O'Leary
Dr S Rossi
Monday, December 02, 2019
Competition Funded PhD Project (Students Worldwide)
Pancreatic adenocarcinoma (PDAC) has the highest rate of death per incidence of any cancer and there have been no significant improvement in survival outcomes in the last 40 years. Currently surgery has the best outcomes for patients, however only about 20% of patients are eligible for surgery at time of diagnosis. Up to a further 40% of patients have locally advanced disease, where the tumour has not spread outside the pancreas but is too large for surgical resection.
Two factors that contribute to the poor clinical outcomes associated with PDAC are the tumour stroma and epithelial-mesenchymal transition (EMT) of cells within the tumour. The tumour stroma in PDAC is a dense extracellular matrix (ECM) composed of fibrillar elements, such as collagen and activated fibroblasts with a recent hypotheses being that the ECM could play a role in therapeutic resistance. According to this hypothesis, the stiffness of the ECM impairs blood vessel perfusion, resulting in a poorly vascularised cancer, which ultimately represents a barrier to drug delivery. This results in a need for higher systemic doses of drugs, leading to increased toxicity and patient morbidity, often with limited efficacy. One approach to overcoming the issue of penetration into the dense stroma is direct intratumoural (IT) injection using Endoscopic Ultrasound-Fine Needle Injection (EUS- FNI). A significant constraint of this approach has been the use of aqueous solutions of a single chemotherapeutic agent. The low viscosity of aqueous solutions provide limited retention and duration of action at the tumour site resulting in rapid clearance and transient effect of the drug.
There is also increasing evidence in PDAC suggesting that EMT generates cells with stem cell properties, promoting the Cancer Stem Cell (CSC) phenotype, and enhancing PDAC tumorigenicity and chemoresistance. Recent evidence has suggested that this chemoresistance is associated with development of the EMT phenotype in tumour cells. These factors in combination are considered to contribute significantly to the poor clinical outcomes observed in the treatment of PDAC.
The Kelly lab has developed a drug delivery platform for direct IT injection, which has been shown to be retained at a tumour site for at least 14 days with the ability to offer sustained release of drugs. The platform has also been shown to have inherent chemoablative properties, which may offer synergistic activity with other therapeutic modalities. This project proposes to use this platform to develop a multi-modal locoregional drug delivery system with a primary aim to reduce tumour burden in PDAC.