Abstract A90: Blocking proinvasive signaling and inflammatory activation in triple-negative breast cancer with nucleic-acid scavengers (NAS)

Abstract

Abstract Breast cancers (BC) remain the most lethal malignancies among women worldwide and the second leading cause of cancer-related mortalities in the US. Subtype heterogeneity and aggressive invasive potential are believed to be the major contributors of these outcomes. BC lacking canonical histologic receptors (i.e., ER/PR/HER2), called triple negative (TNBC), are notoriously aggressive, difficult to treat, and metastatic. It has been observed that the degree of inflammation-driven tumorigenesis tends to correlate with increased levels of cell free DNA (cfDNA) and other damage-associated molecular patterns (DAMPs) in cancer patient sera. Our lab has previously shown that nucleic-acid scavengers (NAS) can block proinflammatory and proinvasive/metastatic signals elicited by nucleic acid-containing DAMP activation of innate immune sensors such as of the Toll-like receptors (TLRs). Recently, we showed that treatment with the nucleic acid-binding polymer, PAMAM-G3, resulted in a drastic reduction in metastatic tumor burden to the liver in an immunocompetent murine model of pancreatic cancer (Naqvi I, Gunaratne R, et al., Mol Ther 2018;26). Ongoing work has shown that chemotherapy-derived TNBC-conditioned media (CM) and TNBC patient sera greatly increase TNBC cell invasion in vitro and that treatment with the NAS PAMAM-G3 significantly inhibits this effect. Treatment of the human monocyte cell line, THP-1, with TNBC CM elicited a very strong proinflammatory response comparable to known innate immune stimulants such as poly(I:C), LPS, and CpG, with elevated levels of IL-8, IL-6, MCP-1 (CCL2), IL-18, and IL-1β. Other biologically relevant immune responders such as isolated human PBMCs and whole blood will be tested to determine the potential impact on the tumor immune microenvironment during tumorigenesis and treatment. To elucidate the mechanism by which this NAS works in these tumor settings, our lab has developed several PAMAM-G3 derivatives, including biotin, IR-, and near-IR fluorophore-labeled molecules. These molecules will allow us to conduct DAMP capture and characterization experiments, as well as perform in vitro and in vivo live imaging experiments to gain insight into NAS PK/PD properties. Mechanistic insight into NAS antimetastatic and anti-inflammatory capabilities will enhance our understanding of metastatic progression and its interplay with the immune system. Moreover, these principles will aid in the development of novel of antimetastatic therapies to improve TNBC patient outcomes. Citation Format: Elias O.U. Eteshola, Karenia Landa, E. Shelley Hwang, Angelo Moreno, Smita K. Nair, Bruce A. Sullenger. Blocking proinvasive signaling and inflammatory activation in triple-negative breast cancer with nucleic-acid scavengers (NAS) [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A90.