Abstract 181: Discovery of novel targeted therapeutics for metastatic breast cancer

Abstract

Abstract Metastatic disease is the primary cause of breast cancer mortality, due to the lack of effective therapy. The Rho GTPase Rac is integral for the promotion of cancer cell migration/invasion, proliferation, and survival. Since metastatic breast cancers often overexpress or exhibit high Rac activity, inhibition of Rac is a viable strategy against metastatic cancer. Recently, we characterized EHop-016, a small molecule that inhibits Rac activity of metastatic breast cancer cells with an IC50 of 1 µM. EHop-016 is 10-100 times more active than previously available Rac inhibitors, and is the first compound shown to inhibit the activation of Rac by the oncogenic GEF Vav. EHop-016 inhibits the activity of the Rac downstream effector p21 activated kinase (PAK), lamellipodia extension, and cell migration of metastatic breast cancer cells. We also reported that EHop-016 at ≥ 25 mg/kg Body Weight (BW) significantly reduced tumor growth, metastasis, and angiogenesis in a mouse model. However, our recent pharmacokinetic study of EHop-016 in a mouse model demonstrated that the bioavailability of Ehop-016 needs to be improved for further pharmacological development. Therefore our hypothesis is that improvement of the EHop-016 structure will provide probes with increased potency against Rac and, therefore, increased bioavailability. Herein we have tested several Ehop-016 derivatives for their effects on breast cancer cell viability and Rac activation. Using MTT assays we found that the Ehop-016 derivatives, HV-107 and HV-118, significantly inhibit the viability of metastatic breast cancer cell lines MDA-MB-231 and MDA-MB-435. The effects of HV-107 and HV-118 on the inhibition of Rac activation were tested by ELISA-based Rac activity assays and pulldown assays. Results show that at 250nM, HV-107 inhibits Rac activation by 55%, whereas HV-118 has a similar effect at 100nM in MDA-MB-231 and MDA-MB-435 cells. Taken together, our findings suggest HV-107 and HV-118 as promising Ehop-016 derivatives with potential as anti-metastatic agents, which should be further characterized. This study was supported by awards from the Susan Komen for the Cure, NIH/NIMHHD U54MD008149, and the Puerto Rico Science and Technology Trust to SD; NIH/NCRR R25GM061838 to UPR MSC; NIH/NIMHHD RCMI 8G12MD007583RCMI, Title V PPOHA 031M10505 and Title V Cooperative P031S130068 from U.S. Department of Education to UCC; and PRINBRE (NIH/NIGMS P20GM103475-13) Pilot Project to LCP. Citation Format: Cristina Del Valle, Eliud Hernández, Cornelis P. Vlaar, Luis A. Cubano, Suranganie Dharmawardhane, Linette Castillo-Pichardo. Discovery of novel targeted therapeutics for metastatic breast cancer [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 181. doi:10.1158/1538-7445.AM2017-181