Abstract 1997: The Rac inhibitors HV-107 and HV-118 as potential therapeutics for metastatic breast cancer
Authors: Velez Grace E. , Vlaar Cornelis , Hernandez Eliud , Valentin Anibal , Castillo-Pichardo Linette , Dharmawardhane Suranganie 
Published: August 2019

Breast cancer is the first cause of death in women globally. Metastatic breast cancer is stimated to affect more than a quarter of million of women in the US. Due to the lack of effective treatment, metastasis remains the main cause of breast cancer mortality. Therefore, it is imperative to develop novel effective strategies against metastasis. A promising target for anti-metastatic therapy is the Rho GTPase Rac because it plays a key role in metastatic cancer progression by regulating cellular processes such as adhesion, migration, proliferation and survival. Our group developed Ehop-016, a small molecule that inhibits Rac in metastatic breast cancer cells with an IC50=1µM and significantly reduces tumor growth, angiogenesis, and metastasis in a mouse model of metastatic breast cancer. However, its relative bioavailability is moderate and should be improved. Therefore, to find a compound with increased potency and bioavailability, we tested several Ehop-016 derivatives. Using Rac pulldown assays we show that HV-107 and HV-118 inhibit Rac activation by 60% in MDA-MB-231 and MDA-MB-435 metastatic breast cancer cells at 100 and 250nM, respectively. MTT assays show HV-107 (at ≥500nM) and HV-118 (at ≥50nM) significantly inhibit metastatic breast cancer cell viability, while showing minimal toxicity towards non-cancerous cells. Cell cycle analysis by flow cytometry demonstrates a G2-M arrest and a prominent sub-G1 population, indicative of cell death, in metastatic breast cancer cells treated with HV-107 (1000 nM) and HV-118 (100 nM). To evaluate apoptosis as a potential cell death mechanism, we measured caspase 3 activity. Our results show HV-107 and HV-118 significantly induce caspase 3 activity by approximately 1.6-fold at 1000 and 100nM, respectively in metastatic breast cancer cells. Therefore, these Rac inhibitors affect cell viability by inhibiting cell cycle progression and inducing apoptosis. Finally, we tested HV-118 (at 1mg/kg BW) in a mouse model of metastatic breast cancer and found a 30% reduction in tumor growth and a 90% inhibition in metastasis. Taken together, our results indicate HV-107 and HV-118 have potential as anti-breast cancer metastasis therapeutics. 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 and PRINBRE (NIH/NIGMS P20GM103475-13) Sub-Award to LCP.

Citation Format: Grace E. Velez, Cornelis Vlaar, Eliud Hernandez, Anibal Valentin, Linette Castillo-Pichardo, Suranganie Dharmawardhane. The Rac inhibitors HV-107 and HV-118 as potential therapeutics for metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1997.