Abstract 4899: The small molecule cathepsin L and K inhibitor KGP-94 impairs the metastatic phenotype of osteosarcoma cells

Abstract

Abstract Osteosarcoma (OS) is the most common primary malignant bone cancer and primarily affects adolescents between the ages 10-20 years old. Today, OS remains the second leading cause of cancer-related death for patients in this age group. With current therapy, the 5-year survival for patients with clinically metastatic disease has remained unchanged at 20% since the early 1970s. There is a significant need for novel therapies that will increase overall survival for patients with metastatic OS. Proteases secreted within the tumor microenvironment enable primary tumor development and potentiate the ability of OS cells to metastasize. Typically, cysteine proteases under normal physiologic conditions function primarily within the lysosome to facilitate protein cell turnover. During tumorigenesis, Cathepsin L (CTSL) is secreted into the tumor environment by the tumor. CTSL secretion potentiates metastasis through its regulation of cell motility, extracellular matrix degradation, angiogenesis, and bone remodeling. Cathepsin K (CTSK) is overexpressed in OS and is secreted during bone remodeling by osteoclast to degrade the bone matrix. The bone environment is hypoxic which induces proteomic changes that enable OS cells to survive in a nutrient deprived environment and increase CTSL/CTSK secretion by the tumor cells. The goal of these studies was to determine if CTSL/CTSK inhibition via KPG-94 (3-bromophenyl-3-hydroxyphenyl-ketone thiosemicarbazone) could decrease the metastatic phenotype of human osteosarcoma cells under normoxic and hypoxic conditions. The Hu09 cell line has been characterized as an osteoblastic cell line with the potential to grow orthotopically in vivo. Hu09 and its metastatic sublines Hu09-L6 and Hu09-M112 have been characterized to low and high metastatic capacity, respectively. Treatment with KGP-94 at 10 and 25 uM effectively decreases cell motility and invasion of Hu09 and its metastatic sublines under normoxic and hypoxic conditions. Our results demonstrate that dual CTSL/CTSK inhibition is effective at decreasing two signature methods of measuring metastasis: 1) cell motility and 2) invasiveness. Targeting CTSL/CTSK may provide a novel therapeutic approach for patients with metastatic OS. Citation Format: Henrietta Fasanya, Dietmar Siemann. The small molecule cathepsin L and K inhibitor KGP-94 impairs the metastatic phenotype of osteosarcoma cells [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 4899. doi:10.1158/1538-7445.AM2017-4899