Abstract 2898: Inhibition of HDAC6 as a novel targeted therapy in breast cancer

Abstract

Abstract The identification and use of biomarkers is critical to guided clinical care. Cancer treatment has made use of many biomarkers to determine which therapeutic avenues are adequate for each patient. For example, the use of Trastuzumab is intimately linked to the presence of HER2/NEU amplification in breast cancers. Previous work from our group established the importance of HDAC6 in maintaining the homeostasis of inflammatory breast cancer cells (IBC). We also reconstructed the HDAC6 regulon using gene expression profile signatures from over 900 primary breast cancers to obtain a biomarker that guide the use of HDAC6 inhibitors towards the right patient group. This method identified a regulon of 162 transcripts as a set of transcriptional targets whose expression is affected by HDAC6 master regulator activity. Finally, the expression of all transcripts that are co-regulated by HDAC6 in the breast cancer samples were integrated into a single score termed as the HDAC6 score. Through this work, we established that HDAC6 score is associated with cancer cell response to HDAC6 inhibitor ACY1215. HDAC6, one of eighteen deactylases, is distinct from all other HDACs as it is located mainly in the cytosol and has non-chromatin substrates such as α-tubulin and HSP90. HDAC6 inhibitors have gained a lot of momentum in the clinic for hematological malignancies and our computational analysis has also revealed that these tumors also exhibit a high HDAC6 score. Therefore, by identifying the HDAC6 score for tumors, we can widen the scope of using HDAC6 inhibitors to a wide range of cancers. Our increasing understanding of tumor biology has led to the use of combinatorial therapies to fully benefit from cancer therapy. This project will encompass the use of combinatorial therapy containing HDAC6 inhibitors and paclitaxel to demonstrate an increased potential in treating breast cancer. These studies will closely mirror the clinical trial that we are undertaking with our collaborators from Acetylon where metastatic breast cancer patients are being treated using HDAC6 inhibitor ACY1215 in combination with nab-paclitaxel (NCT02632071). This project aims to provide the frame work to utilize for the first time the HDAC6 score as a marker for identifying tumors that will be most susceptible to HDAC6 inhibition in the clinic. Citation Format: Tizita Z. Zeleke, Preeti Putcha, Jiyang Yu, Andrea Califano, Jose M. Silva. Inhibition of HDAC6 as a novel targeted therapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2898.