Abstract A155: The Rac and PAK inhibitor EHop-016 inhibits mammary tumor growth and metastasis in a nude mouse model.

Abstract

Abstract The Rho GTPase Rac is a central regulator of cancer cell migration/invasion that has been implicated with cancer metastasis. Therefore, we designed and developed small molecule compounds that specifically target Rac in metastatic cancer cells. We recently reported the characterization of EHop-016 as a Rac inhibitor in metastatic cancer cells, where EHop-016 was shown to inhibit Rac activity with an IC50 of 1 μM. At higher concentrations (>10 μM) EHop-016 reduced cell viability and inhibited the related Rho GTPase Cdc42, but not Rho. EHop-016 decreased the activation of Rac by the oncogenic guanine nucleotide exchange factor Vav, the activity of the Rac effector p21-activated kinase (PAK), and the extension of actin cytoskeletal structures and migration of metastatic cancer cells. Next, we determined the efficacy of EHop-016 in vivo, using a mouse model of experimental metastasis. Green fluorescent protein (GFP) tagged MDA-MB-435 human metastatic cancer cells were inoculated at the mammary fat pad of nude mice and treated with 0, 5, 10, 25, or 40 mg/kg body weight (BW) EHop-016 3X a week for ∼8 weeks. Mammary tumor growth and metastases in lungs, spleens, kidneys, livers, hearts, and femurs were quantified by fluorescence image analysis. At concentrations >10 mg/kg BW, EHop-016 significantly inhibited mammary tumor growth and metastasis to distant organs. EHop-016 had no effect on mouse weight or their gross phenotype, indicating that EHop-016 did not exert toxic effects in athymic nude mice. This data demonstrate that EHop-016 and derivatives hold promise for further development as targeted anti-cancer therapeutics. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A155. Citation Format: Linette Castillo-Pichardo, Tessa Humphries-Bickley, Eliud Hernandez, Columba de la Parra, Luis Cubano, Cornelis Vlaar, Surangani F. Dharmawardhane Flanagan. The Rac and PAK inhibitor EHop-016 inhibits mammary tumor growth and metastasis in a nude mouse model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A155.