Abstract 901: The mechanobiome of pancreatic cancer: a viable, targetable drug space

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an annual mortality rate of 37,000 in the US alone. Its 5-year survival rate of ~6% remains relatively unchanged over the past 4 decades. Because PDAC has elevated rates of de novo and acquired resistance to traditional chemotherapies, we are exploring new drug spaces that target metastatic hepatic disease, the primary mortality factor for patients. Specifically, we have identified the cluster of proteins that sense and respond to mechanical stimuli - collectively known as the mechanobiome. This cytoskeletal machinery is responsible in large part for endowing metastatic cells with the ability to navigate through different tissue types. Based on their mechanoresponsiveness profile, we have predicted and identified via western blot and immunohistochemistry proteins in the mechanobiome that are upregulated in patient-derived pancreatic tissues. These proteins include non-muscle myosin IIA and IIC, alpha-actin-4, and filamin B. We are performing knockdown and overexpression studies of these isoforms on 2D and 3D behaviors - cell mechanics, migration, invasion, and tissue sphere formation and are poised to begin mouse studies on the metastatic sufficiency in altering the expression of these proteins. In addition, we are testing 4-HAP, a small molecule mechanics modulator that we previously identified that targets myosin IIC, thus affecting PDAC mechanics in PDAC murine models. Limited studies reveal that 4-HAP reduces metastasis. These data suggest that direct targeting of the mechanobiome may eventually expand treatment strategies for pancreatic cancer. Citation Format: Alexandra Surcel, Eric S. Schiffhauer, Dustin Thomas, Qingfeng Zhu, Robert Anders, Douglas Robinson. The mechanobiome of pancreatic cancer: a viable, targetable drug space [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 901. doi:10.1158/1538-7445.AM2017-901