Abstract 3922: Novel hepatocyte growth factor and macrophage stimulating protein antagonists for the treatment of castration-resistant prostate cancer

Abstract

Abstract Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer that is refractory to androgen deprivation therapy and characterized by aggressive growth, extensive metastasis formation, and poor prognosis. CRPC is temporarily manageable by the first-line chemotherapeutic docetaxel, but will eventually progress as a chemoresistant cancer, prompting a need for additional therapeutics to either replace docetaxel or to be used in combination therapies that increase the effectiveness of chemotherapy. The aberrant activation of the tyrosine kinase receptor c-Met by the active, dimeric form of hepatocyte growth factor (HGF) and the tyrosine kinase receptor RON by macrophage stimulating protein (MSP) results in the overactivation of signaling pathways that encourage cell proliferation, migration, and survival, contributing to the malignant behavior and chemoresistance of many cancers. The onset of metastatic prostate cancer is associated with both increased serum levels of HGF and expression of c-Met and RON in metastatic growths. Our laboratory has developed small molecules that inhibit HGF dimerization, c-Met activation, and malignant cell behaviors in several cancer cell types. Considering the high degree of homology between HGF and MSP, we predict that our strategy for inhibiting the activation of HGF can be extended to develop compounds that dually inhibit HGF and MSP. We hypothesize that inhibiting HGF and MSP with our antagonists will correspondingly reduce activation of c-Met and RON and suppress tumor growth and metastasis in CRPC. We further anticipate a therapy that combines our antagonists and docetaxel will increase the efficacy of chemotherapy by blunting the pro-survival properties of the HGF/c-Met and MSP/RON systems. Preliminary results indicate that our HGF dimerization antagonist Norleual [Nle-Tyr-Ile-ψ-(CH2-NH2)3-4-His-Pro-Phe] significantly inhibits the migration of CRPC cells and increases their susceptibility to docetaxel treatment in vitro. The primary objective of this study is to investigate the feasibility of HGF, MSP, and HGF/MSP dual antagonists as a therapy for CRPC either alone or in combination with docetaxel. Citation Format: Brett Vanderwerff, Kevin Church, Leen Kawas, Joseph Harding. Novel hepatocyte growth factor and macrophage stimulating protein antagonists for the treatment of castration-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3922. doi:10.1158/1538-7445.AM2015-3922