Abstract NTOC-084: THE PROMISE OF COMBINATIONAL TREATMENT OF HISTONE DEACETYLASE 6 INHIBITOR ACY-1215 AND PROTEASOME INHIBITOR BORTEZOMIB IN SCCOHT
Authors: Chen Yuting Shary , Wang Yemin , Karnezis Anthony , Ramos Pilar , Yine Holly , Weissman Bernard , Trent Jeffrey , Huntsman David 
Published: June 2017

PURPOSE: Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a rare ovarian cancer that predominantly affects young women with a median age of 24 years. Although half of the tumors are diagnosed at an early stage, the prognosis is dismal due to lack of effective treatment options. In response to drastic increase of protein translation and cellular stress during malignant transformation, cancer cells have evolved to highly depend on protein surveillance pathways to correct or degrade unfolded and misfolded proteins to ensure protein homeostasis. Inhibition of these protein surveillance pathways has been proven to selectively target cancer cells. Particularly, inhibition of proteasome, which degrades more than 80% of cellular proteins, by selective inhibitors leads to accumulation of its substrates and consequently results in activation of apoptotic pathways in highly proliferative cancer cells. However, resistance occurs frequently. As a result several combinational treatments have been investigated in clinical trials with various drugs, such as HDAC6 inhibitor, which shuts down the aggresome-mediated proteolysis. Therefore, we aimed to determine the promise of inhibiting both protein degradation pathways as a novel therapeutic strategy for SCCOHT.

EXPERIMENTAL PROCEDURE: Concentration-effect relationships were determined for both proteasome and HDAC6 inhibitors, alone or in combination, in SCCOHT cell lines and other ovarian carcinoma cell lines using a 3-day cell viability assay measured by crystal violet staining. Cell apoptosis was measured by live cell imaging with activated caspase-3/7. Drug action mechanism was interrogated by Western blotting.

RESULT: SCCOHT cells are hypersensitive to both proteasome inhibitor (Bortezomib) and HDAC6 inhibitor (ACY-1215) with IC50 around low nM and μM, respectively. In addition, both Bortezomib and ACY-1215 inhibited cell proliferation and induced apoptosis in SCCOHT cells. Treatment with ACY-1215 led to inhibition of the aggresome as evidenced by an increased level of acetyl-tubulin, accumulation of polyubiquitinated proteins and upregulation of the unfolded protein response. Combination of Bortezomib and ACY-1215 led to an increased level of poly-ubiquitinated proteins, stronger suppression of cell proliferation and more apoptosis compared to either drug alone in SCCOHT cells, with some dosing having synergistic effect.

CONCLUSION: Our data suggest that ACY-1215 or Bortezomib alone significantly suppressed the growth and induced apoptosis of SCCOHT cells. Combination of ACY-1215 and Bortezomib synergistically increased growth suppression and cell apoptosis and thereby may be a potential rational therapeutic strategy for SCCOHT.

Citation Format: Yuting Shary Chen, Yemin Wang, Anthony Karnezis, Pilar Ramos, Holly Yine, Bernard Weissman, Jeffrey Trent, David Huntsman. THE PROMISE OF COMBINATIONAL TREATMENT OF HISTONE DEACETYLASE 6 INHIBITOR ACY-1215 AND PROTEASOME INHIBITOR BORTEZOMIB IN SCCOHT [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-084.