Novel LXR/ER modulator as a polypharmacological agent against Breast Cancer

AMADO L; PALAVECINO M; MEDRANO PILAR; CARCAGNO A; BURTON G; PECCI A; DANSEY V

MAR DEL PLATA

Congreso; LXIV reunión anual de la Sociedad Argentina de investigaciones clínicas; 2019

SAIC

Breast Cancer (BC) is a complex disorderdue to multiple genes deregulation, which prompts a robustphenotype. The pharmacological paradigm of ?magic bullets?,targeting individual chemoreceptors, fails as redundant functionsare activated and alternative compensatory signaling routessustain the tumor phenotype, leading to immune escape,chemoresistance and metastasis. In this way, polypharmacologyarises as a new paradigm: designing multifunctional drugs that,selectively, interact with several molecular targets. This approachwould tackle several signaling and metabolic routes at the sametime, with one drug, leading to new and more effective treatmentagainst BC. Our hypothesis is that a dual antagonist of both,Estrogen Receptor (ER) and Liver X Receptor (LXR), would inhibitthe ER canonical survival routes, but also would inhibitlipogenesis and Warburg effect through LXR antagonism. Thesetwo are key metabolic pathways that drive cancer progression,growth, survival, immune evasion, resistance to treatment anddisease recurrence. In this sense, we performed a screening ofdifferent natural and synthetic oxysterols where Compound 1emerged as a promising compound. Our unpublished findingsproved it is a dual ERalpha/ERbeta; antagonist at micro molarconcentration, and a dual LXRalpha;/LXRbeta; inverse agonist atmicro molar concentration, in reporter gene assays. 1 effectivelyinhibits proliferation and migration on the ER+ BC cell line MCF7 and the ER- BC cell line MDA-mb-231. Moreover, it inhibitsmigration of the human vascular endothelial cell line EA.hy926,by suppressing the NFkB signaling pathway, suggestingantiangiogenic activity. Furthermore, 1 is a natural product,easily obtained in high yields and high degree of purity from awild plant. We present our preliminary studies on 1, with the finalintention of validating the dual ER/LXR modulation as a target forpolypharmacological agents anti-BC.