Xiaonan Zhang

Albacarcin V adds EPLIN as a novel and promising target for the treatment of female cancers and pediatric medulloblastoma

Breast and ovarian cancers remain among the most lethal malignancies affecting women worldwide. Despite advances in standard therapies, drug resistance and high relapse rates continue to undermine long-term treatment outcomes. To address these challenges, we re-evaluated five previously identified drug candidates (FLIX1-FLIX5), all of which are effective at nanomolar concentrations in breast and ovarian cancer cell lines. Among them, FLIX3 (Albacarcin V) and FLIX4 exhibited the most potent cytotoxicity, with IC50 values below 50 nM across multiple cell lines. Notably, FLIX3 also exhibited nanomolar-range efficacy in drug-resistant, patient-derived samples from triple-negative breast cancer (TNBC) and ovarian cancer. In a zebrafish model, FLIX3 effectively eliminated cancer cells within its safety window. ATAC-Seq analysis revealed that both compounds induce significant epigenetic alterations. Proteome Integral Solubility Alteration (PISA) and cellular thermal shift assay (CETSA) identified EPLIN (Epithelial Protein Lost in Neoplasm) as the top target of FLIX3 but not FLIX4. EPLIN was previously identified as the primary target of FLIX5. Its re-emergence as the dominant target of FLIX3 highlights its potential as a broadly applicable therapeutic target. Collectively, these findings support the continued development of EPLIN-targeting compounds as promising agents for treating aggressive and drug-resistant breast and ovarian cancers.

Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries

Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A, a member of the SWI/SNF chromatin-remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells; however, the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here, we show that ARID1A loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated with increase in c-Myc expression and increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 showed it extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide for the targeting mitochondrial activity in ARID1A-mutated OCCCs.