Targeting Intrinsic and Extrinsic Barriers to Treat Metastatic Pancreatic Cancer

University Of Rochester, Rochester NY

Investigators

Abstract

Pancreatic ductal adenocarcinoma (PDAC) owns the ominous ranking as the most lethal malignancy of all major cancers. These dismal survival rates can be largely attributed to specific intrinsic and extrinsic barriers that foster metastatic dissemination and impart treatment resistance. Our group and others have demonstrated that epithelial to mesenchymal transition (EMT), a cellular program intrinsic to tumor cells, promotes metastases and is a major barrier to treatment efficacy. However, an additional extrinsic barrier exists, notably a signature immunosuppressive tumor microenvironment (TME) that not only inhibits most anticancer therapies, but also exacerbates the progression of EMT. This proposal will test the overarching hypothesis that both barriers must be targeted in order to develop an effective therapy against metastatic PDAC. To accomplish this, our laboratories have investigated an alternative treatment strategy that administers a therapy directly to the TME consisting of local radiotherapy and intratumoral immunotherapy. This innovative approach would concentrate the therapeutic payload to the tumor specifically, which we hypothesized could overcome the immunosuppressive properties of the PDAC TME. To test this, a novel nanotechnology was generated where a modified monomeric mRNA sequence of the potent immunostimulatory cytokine interleukin-12 (IL12) was encapsulated in a lipid nanoparticle (LNP) specifically designed to maximize intratumoral uptake and endosomal release of the ribonucleic acid when administered directly to the TME. This immunotherapeutic was combined with localized stereotactic body radiotherapy (SBRT); an emerging radiotherapeutic for the treatment of PDAC, which augments the efficacy of immunotherapy. The treatment schedule of SBRT (6Gy/day over 4 consecutive days) followed by an intratumoral injection of IL12mRNA resulted in remarkable tumor elimination and long-term survival in multiple preclinical models of PDAC. The success of this local combinatorial approach was attributed to a profound repolarization of the PDAC TME that was now capable of supporting potent antitumor T cell responses. However, we discovered that although SBRT/IL12mRNA was effective in eliminating metastatic disease in 70% of mice, 30% of the tumors experienced treatment resistance due to tumor cell mesenchymal transition. These results suggest that reversing tumor cell EMT will maximize SBRT/IL12mRNA efficacy and overcome both extrinsic and intrinsic barriers to effective systemic therapy. Aim I will investigate CD4 T cells; a subset of antitumor effector cells generated in response to SBRT/IL12mRNA treatment, which we hypothesize are essential to “condition” distal metastases, mediating systemic immunity. Aim II will test a novel therapeutic targeting Netrin-1 (NP137), a potent inducer of EMT in PDAC tumor cells, and determine how inhibiting mesenchymal transition overcomes treatment resistance to SBRT/IL12mRNA therapy. This proposal will guide the development of a new generation of therapies that emphasize both the repolarization of arduous TMEs (an extrinsic factor), but also the reversal of the mesenchymal phenotype intrinsic to the PDAC tumor cell.