Abstract LB-C11: Targeting metastatic prostate cancer with a multi-functional therapy approach

Abstract

Abstract Prostate cancer (PCa) cells move throughout the body, hone to and destroy the bone microenvironment, grow and thereby cause death. Our historical inability to target cell movement has precluded our realization of multifunctional therapy wherein each of these processes is targeted. Our group has recently shown that inhibition of intracellular activation of Raf1 with the small molecule therapeutic, KBU2046, permits for the first time selective inhibition of cell motility. Here we demonstrate that simultaneous disruption of multiple distinct functions that drive progression of PCa to induce death results in advanced disease control. Using an orthotopic murine model of human PCa metastasis, KBU2046 combined with docetaxel achieves sustained anti-tumor action and improved inhibition of metastasis, compared to monotherapy. KBU2046 does not interfere with androgen deprivation or androgen receptor antagonist mediated hormone therapy in either in vitro or in vivo models. Cell movement is necessary for osteoclast-mediated bone degradation. KBU2046 inhibits Raf1 and its downstream activation of MEK1/2 and ERK1/2 in osteoclasts, inhibiting cytoskeleton rearrangement, resorptive cavity formation and bone destruction in vitro, with improved effects observed when the bone microenvironment is chemically modified by pretreatment with zoledronic acid. Using a murine cardiac injection model of human PCa bone destruction quantified by computed tomography, KBU2046 plus zoledronic acid exhibited improved inhibitory efficacy, compared to monotherapy. The combined disruption of pathways that drive cell movement, honing to the bone and growth constitutes a multi-functional targeting strategy that provides advanced disease control. Citation Format: Ryan Gordon, Limin Zhang, Abhinandan Pattanayak, Wenqi Li, Raymond Bergan. Targeting metastatic prostate cancer with a multi-functional therapy approach [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-C11. doi:10.1158/1535-7163.TARG-19-LB-C11