Abstract B050: The role of activated beta-catenin/Wnt signaling in the progression of castration resistance of prostate cancer in bone

Abstract

Abstract Bone metastases typically develop in patients with advanced prostate cancer (PCa). These metastases are osteoblastic (bone-forming) and constitute the main cause of morbidity and mortality. Androgen deprivation is commonly used to treat bone metastases of PCa, but responses to such therapy are short, and eventually the disease progresses to a castration-resistant form. Bone is the primary site of castration-resistant PCa (CRPC) progression. Further development of therapies for bone metastases of PCa requires an understanding of the mechanisms underlying the growth of CRPC in bone. Clinical and laboratory-based investigations have implicated a role for PCa cell-bone cell interaction in the growth of PCa and have demonstrated that osteoblasts produce factors that favor the growth and survival of PCa cells. Collectively, these observations strongly suggest that PCa cells interact with osteoblasts and that this interaction contributes to the growth of PCa in bone. Recently, a study showed 18% of patients with metastatic CRPC harbored alterations in the Wnt canonical pathway, including hotspot mutations of β-catenin (β-cat), the molecular node of the Wnt canonical pathway, that leads to pathway activation. This report is in agreement with previous publications of β-cat nuclear accumulation, an indirect measure of Wnt-canonical pathway activation, in 20 to 40% of advanced PCas. We previously reported that a patient-derived xenograft (PDX) MDA-PCa-118b (118b) developed in our lab harbors a β-cat mutation (D32G) and has an activated Wnt canonical pathway. 118b induces an osteoblastic reaction when it is implanted in the bone of mice in vivo. In vitro, 118b induces osteoblast proliferation in coculture. In contrast, the PCa cell line, PC3, induces osteolytic lesions in vivo and in vitro inhibits osteoblast proliferation in coculture. Strikingly, expression of β-cat mutated at D32G in PC3 cells reverses the osteoblast inhibitory effect of PC3 cells, resulting in increased proliferation of osteoblasts when grown in coculture. We therefore hypothesize that β-cat/Wnt signaling in PCa cells mediates the PCa-bone interaction that favors PCa growth in bone. Our future studies are focusing on studying the importance of β-cat mutations recently identified in patients with metastatic CRPC and determining whether these mutations also result in an osteoblastic phenotype, which in turn supports growth of prostate cancer in bone. Additionally, we are screening our collection of PCa PDX lines for increased β-cat expression through immunohistochemistry and will sequence DNA from PDX lines that demonstrate increased nuclear β-cat expression to test for activating mutations in β-cat. Our aim is to gain insight into the mechanism of the paracrine interaction between PCa cells and bone that supports the growth of PCa bone lesions, with the ultimate goal of developing therapies to block these interactions and reducing the morbidity and mortality associated with metastatic disease. Citation Format: Justin M. Roberts, Estefania Labanca, Peter Shepherd, Jun Yang, Michael W. Starbuck, Nora M. Navone. The role of activated beta-catenin/Wnt signaling in the progression of castration resistance of prostate cancer in bone [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B050.