The investigation of synergistic drug combinations in breast and ovarian cancer

Abstract

Breast cancer (BC) continues to be a significant cause of female mortality worldwide, resulting in 0.6 million annual deaths. Among its subtypes, Triple-Negative Breast Cancer (TNBC), lacking targetable receptors, stands out as an especially aggressive type. While targeted therapy and chemotherapy are standard treatments for BC, the absence of targetable receptors in TNBC makes chemotherapy the primary treatment option for this BC subtype. Identification of specific drug targets to treat TNBC remains a major unmet clinical need.

HDAC6 has emerged as a potential target for cancer treatment due to its overexpression in various cancers, including breast cancer. Although the HDAC6 selective inhibitor, ACY-1215, has not been shown to effectively kill breast cancer cells, the potential for combination therapy with HDAC6i holds promise for cancer treatment. In this thesis, we used in silico analysis to investigate the combination of cisplatin with ACY-1215 in TNBC cells. Despite HDAC6i sensitising cells to cisplatin, a synergistic effect was not observed. Following this, a high-throughput method screening was employed in this study. A 593 preprinted drug library was applied to the MDA-MB-231 TNBC cell line, with or without ACY-1215, to measure synergising drug combinations arising from HDAC6i. Disulfiram, an ALDH1 inhibitor used to treat alcoholism, was found to have a synergistic effect with ACY-1215 in both 2D and 3D models of TNBC.

Ovarian cancer (OC) is also a highly malignant disease affecting women worldwide. High grade serous ovarian cancer (HGSOC) makes up most ovarian cancer cases and has the lowest survival rates. Identifying more effective drugs for the treatment of ovarian cancer is crucial. Drug repurposing, also known as drug repositioning or reprofiling, involves finding new uses for existing medications or investigational drugs beyond their original medical indication. This approach offers several advantages over conventional drug discovery, including reduced costs, time, and risk, as much of the preclinical and phase I/II work has already been completed. The cytotoxicity of the 593-drug library was tested in three HGSOC cell lines and the results identified five drugs with potent cytotoxicity at 500 nM and 14 drugs were cytotoxic at 1 μM. To explore better treatments for HGSOC, we have developed an advanced high-content drug screening protocols to screening for cytotoxic drug combinations, MuSIC, which is a multiplex screening protocol for interacting compounds (MuSIC). Following screening for interacting drug combinations at 0.5 mM and 1 mM, the bliss model was applied to select synergistic combinations. Ten novel drug combinations not previously described in the treatment of HGSOC were identified. Future research will focus on developing preclinical data to support clinical testing of these drug combinations.

Thesis is embargoed until 31 July 2029.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Fiona Furlong (Supervisor) & Irina Tikhonova (Supervisor)