Abstract PS16-11: Potential therapeutic effects of HDACi FK228 on TNBC using various models

Abstract

Abstract Breast cancer is the most prevalent type of cancer among women. Most breast cancers are hormone sensitive, however triple negative breast cancer (TNBC), a more aggressive subtype of breast cancer is characterized by its negative expression of estrogen and progesterone receptors, and lack of Her2/NEU amplification. Because of its receptor status, hormone receptor targeted treatments are ineffective against TNBC making it difficult to treat. FK228, known as Romidepsin, is a histone deacetylase inhibitor (HDACi) that specifically targets the enzymes HDACs 1 and 2, tumor suppressor and other proteins exerting epigenetic changes on tumor cells resulting in anticancer activity. FK228 has not been studied in TNBC, but has been approved by the FDA for the treatment of peripheral T-cell lymphoma (PTCL), where the mechanism of action has demonstrated cell cycle arrest and apoptosis [1,2]. To assess the preliminary role of FK228 in breast cancer, a number of TNBC cell lines were treated with the drug and analyzed for suppression of cell cycle genes. Similar to PTCL, TNBC cell lines showed an increase in cell cycle arrest genes such as p21 and others subsequent to treatment. Moving forward, to recapitulate the tumor microenvironment we have utilized 2D and 3D culture, while PDXs (patient derived xenografts), an excellent translational tool. We first identified changes in morphology and migration in 2k1, MDA-MB 231 and HS-578t cell lines treated with FK228 under in-vitro conditions. Additional molecular studies also show a reversal of the epithelial to mesenchymal transition (EMT) in FK228 treated BC cell lines; specifically in relation to EMT genes CDH1 and ZEB2, both directly connected to HDAC1/2 activity. To further study the effects of FK228, PDXs are implanted into mice to study growth patterns, recurrence, metastatic potential and response to FK228 in different patient tumor models. FK228 showed a drastic suppression in tumorigenesis in model TU-BCX-2O0, prompting the study of several other models in tumorigenesis including TU-BX-4IC, 4M4 and 4QX. Metastasis was also monitored by H&E staining lung and liver tissue for analysis for each model, and using an in vivo model consisting of GFP/luciferase transfected breast cancer cells MDA-MB-231 and SUM-159 to monitor both the proliferation and spread of disease in mice. Ultimately this study aims to characterize the FK228 alteration of pathways involved in tumorigenesis, metastasis and resistance within TNBC. Citation Format: Madlin Alzoubi, Khoa Nguyen, Katherine Hebert, Margarite Matossian, Hope Burks, Bridgette Collins-Burow, Matthew Burow. Potential therapeutic effects of HDACi FK228 on TNBC using various models [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-11.