Abstract 4492: Deferiprone optimization for the treatment of triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) is the leading cause of new cancer cases and the second leading cause of cancer deaths in American women disproportionately affecting Black and Hispanic women under 40. Currently, there is no targeted therapy for TNBC and treatment options to manage this lethal disease include surgery, adjuvant chemotherapy and radiotherapy. Among the chemotherapy agents, combination of the PARP inhibitors with DNA-damaging results in a more promising anti-tumor effect. A better understanding of TNBC etiology has aided in unraveling the roles of two additional cellular targets - androgen receptor (AR) and histone lysine demethylase (KDM) - in the viability and survival of TNBC. Interestingly, AR overexpression is the most important driver of prostate cancer (PCa). A class of current medications used to treat PCa act as androgen receptor (AR) antagonists (or antiandrogens). Antiandrogens are under investigation in the clinic as potential therapies for luminal AR (LAR) subtypes of TNBC, a particularly worrisome subtype that frequently metastasizes to regional lymph nodes and bones. Although LAR TNBC constitutes 15-20% of TNBCs, it is characterized by minimal response to chemotherapy and aggressiveness. It is therefore plausible to repurpose and optimize antiandrogens, in the context of designed multiple ligands; to obtain a TNBC-targeting therapy effective against several subtypes of this heterogenous disease, including the basal subtype that is responsible for ~80% of TNBC incidence. The proposed therapeutics are dual-acting antiandrogen-KDM inhibitors. The antiandrogen moiety of these agents will enable TNBC cell-targeting and translocation of the drug into the nucleus where inhibition of KDM will prevent transcription of KDMs that promote tumor growth. The three pharmacophores of these agents are (i) an AR binding group, (ii) a linker, and (iii) an iron-binding group. Two functional classes of these compounds, alkyl- and aryl-derivatives, vary in the design of the AR binding moiety. To optimize these agents, the methylene linker length is varied in each class for in vitro determination of the optimal length for increased drug efficacy. The compounds are tested on TNBC cell lines (MDA-MB-231, low AR+; and MDA-MB-453, high AR+), and ER+ BCa (MCF-7) while PCa cell lines (LNCaP PCa, AR+; and DU 145, PCa, AR-) serve as controls for AR dependency of the compounds. Longer linker length compounds exhibited low micromolar cytotoxicity and selectivity for AR+ TNBC and PCa cell lines. Further analysis of lead compounds in TNBC cells aided in understanding the effects on targets, transcriptomic effects via RNA sequencing analysis and the mechanism of action. Thus far, the designed dual-acting therapeutics have potential to revolutionize the design of anticancer drugs and improve treatment outcome for TNBC patients. Citation Format: Alexis Johnston, Adegboyega K. Oyelere. Deferiprone optimization for the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4492.