Abstract A17: Challenging pancreatic ductal adenocarcinoma and its stroma by a combination of chemo and gene therapy: A preclinical study

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy still characterized by unacceptable prognosis (Malvezzi et al., 2014). Treatments include surgery, chemotherapy, radiation therapy, and palliative care and the most appropriate option is selected depending on the stage of PDAC (Kamisawa et al., 2016; Vincent et al., 2011). Among the most important factors contributing to the failure of treatments, a pivotal role is played by a pronounced desmoplastic stromal reaction composed by extracellular matrix (ECM), blood vessels, endothelial cells, connective tissue elements such as tumor-associated fibroblasts (TAF), immune cells and soluble proteins such as cytokines and growth factors (Erkan et al., 2012; Horimoto et al., 2012; Kalluri and Zeisberg, 2006). Therefore, next to selective PDAC-targeting agents, approaches able to modify PDAC microenvironment may impact tumor/stroma interactions allowing a better therapeutic profile (Bijlsma et al., 2015). For 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 anticancer agent TRAIL (sTRAIL) (Spano et al., 2019; Rossignoli et al. 2019). Gene-modified AD-MSC delivering sTRAIL can reshape the PDAC microenvironment inducing tumor cell apoptosis (Schug et al. 2018; 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 and nab-paclitaxel as prerequisite for a phase I/II clinical trial. Next to 2D cytotoxicity assays, complex 3D in vitro models, mimicking the structure of PDAC, demonstrated a relevant cytotoxic effect exerted by AD-MSC sTRAIL when given alone or in combination with gemcitabine and nab-paclitaxel against BxPC-3; MiaPaca-2 and PATU8988T cell lines. In particular, the pretreatment with nab-paclitaxel reverted the molecular mechanisms related to TRAIL-resistant PDAC cell line. The synergistic effect between gemcitabine and AD-MSC sTRAIL has been further demonstrated in two orthotopic mouse models, in which mice bearing pancreatic cancer received 2 weekly doses of gemcitabine (50 or 100 mg/kg) followed by AD-MSC sTRAIL intratumoral eco-guided injections. Animals treated by this combinatory approach showed a massive destruction of pancreatic malignant tissue and its stroma, visible as hypoechoic regions by ultrasound imaging system. Collectively, these results indicate the powerful potential of combining a gene therapy approach with chemotherapy, suggesting the transferability of an anticancer MSC-based approach in patients affected by PDAC. Citation Format: Giulia Grisendi, Massimiliano Dall'Ora, Angela D'Esposito, Giulia Casaria, Carlotta Spano, Filippo Rossignoli, Giulia Golinelli, Olivia Candini, Massimo Dominici. Challenging pancreatic ductal adenocarcinoma and its stroma by a combination of chemo and gene therapy: A preclinical study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A17.