Targeting pancreatic ductal adenocarcinoma & its stroma by a chemo & gene therapy strategy

Abstract

Background & Aim PDAC is the fourth leading cause of cancer death and it is characterized by a mortality rate higher than 90% (Malvezzi et al., 2014). Despite the progress in the use of improved diagnostic methods and development of novel targeted therapies, the overall survival rate has not improved over the last decade with a 5-year survival rate settled around 8% (Siegel et al., 2016). This poor clinical outcome is partially due to a pronounced desmoplastic stromal reaction characterized by a large amount of extracellular matrix and tumour associated fibroblasts (TAF). This highly fibrotic stroma makes an important contribution to PDAC development, progression and drug resistance (Becker et al., 2013; Xu et al., 2014). Since years, we have been developing a gene-therapy strategy based on adipose derived mesenchymal stromal cells (AD-MSC) to deliver the novel variant of the potent anti-cancer agent TRAIL (sTRAIL) (Spano et al., 2019; Rossignoli et al. 2019). Gene modified AD-MSC delivering sTRAIL can reshape the PDAC microenvironment inducing tumour cell apoptosis (Spano et al. 2019). Starting from this concept, we here challenged the gene therapy approach in combination with standard anti-PDAC agents, such as Gemcitabine&Nab/Paclitaxel, as pre-requisite for a phase I/II clinical trial. Methods, Results & Conclusion By a three-dimensional (3D) in vitro platform combining tumor cells and primary TAF isolated from human PDAC specimens, we recreated in vitro a 3D tumor cell culture mimicking the in vivo tumor. This 3D model allows to generate proof-of-concept data for the trio combination GEM&Nab/PTX and AD-MSC sTRAIL in order to support the rationale of this combinatory approach in PDAC patients. Using three PDAC cell lines, with different sensitivity to chemotherapeutics and TRAIL, we represented the tumor complexity and the possible variability of clinical scenario. Our results demonstrated a relevant cytotoxic impact exerted by AD-MSC sTRAIL both alone or in combination with GEM&Nab/PTX against TAF and PDAC cells. The synergistic effect between GEM&Nab/PTX and AD-MSC sTRAIL has been further demonstrated in an orthotopic mouse model, in which mice bearing pancreatic cancer received 2 weekly doses of chemotherapeutics followed by AD-MSC sTRAIL intra tumoral eco-guided injections. These in vitro and in vivo data demonstrated a powerful potential of combining a gene therapy approach with chemotherapy and suggesting the transferability of an anticancer MSC-based approach in patients affected by PDAC.