Biology subjects

Chua, M.-S.

Publications and source records attributed to Chua, M.-S..

4 recordsLinked to original sources

bioRxiv2026

A Niclosamide Prodrug SSL-0024 with Enhanced Bioavailability Suppresses Hepatocellular Carcinoma via Multi-Pathway Signaling Inhibition

BackgroundHepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for effective therapies. The FDA-approved anthelmintic, niclosamide, is a promising repurposed drug candidate for HCC; however, its clinical application in solid tumors is hampered by poor aqueous solubility and resulting low bioavailability. MethodsWe designed and screened eight novel niclosamide prodrug candidates for solubility, stability, and anti-proliferative activity in HCC cell lines. The lead compound, SSL-0024, was evaluated for pharmacokinetics and anti-tumor efficacy in an orthotopic patient-derived xenograft (PDX) model, and for cytotoxicity in patient-derived organoids (PDOs). Mechanistic studies assessed AKT-mTOR-STAT3 and other related signaling pathways. ResultsThe O-sulfate derivative, SSL-0024, demonstrated improved solubility and pH stability, and a sustained release of niclosamide over [~]48 h. Once-daily oral administration of SSL-0024 (100 mg/kg) achieved [~]60% tumor growth inhibition in PDX models at [~]46.8% of the niclosamide ethanolamine dose, with minimal toxicity. It also induced significantly greater cytotoxicity than sorafenib (p<0.05) in the PDO. Mechanistically, SSL-0024 suppressed major oncogenic pathways including AKT-mTOR-STAT3, RAF, and Wnt/{beta}-catenin. ConclusionsSSL-0024 overcomes key pharmacokinetic limitations of niclosamide while maintaining potent anti-tumor activity, supporting its further development as an orally bioavailable therapeutic candidate for HCC.

cancer biology↗

bioRxiv2024

Niclosamide Prodrug Enhances Oral Bioavailability and Targets Vasorin-TGFβ Signaling in Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) ranks third in cancer-related deaths worldwide, with limited therapeutic options. While niclosamide (NIC) has shown potential for repurposing in HCC, its poor water solubility and low bioavailability limit its efficacy, and its mechanisms of action are not yet fully elucidated. MethodsWe designed a water-soluble NIC prodrug (NIC-PS) and evaluated its efficacy through in vitro and in vivo studies, including pharmacokinetic (PK) and pharmacodynamic (PD) assays, HCC patient-derived xenograft (PDX) models were applied in two independent experiments, vasorin (VASN) knockout models, and combination treatments with NIC-PS and sorafenib or anti-PD-L1 antibody. Bioinformatic analyses and western blotting were used to investigate NIC-PSs target, VASN, and related signaling pathways. ResultsNIC-PS exhibited a ten-fold increase in oral bioavailability and reduced tumor volume by over 75% in HCC PDX models. NIC-PS directly binds and suppresses VASN, suppressing TGF{beta} signaling and reducing SMAD2/3 phosphorylation. VASN inhibition led to a 50% tumor reduction, and NIC-PS enhanced responses to sorafenib and anti-PD-L1 therapy. ConclusionsNIC-PS, equal to 36% of NIC in molecular weight, offers improved bioavailability, efficacy, and a novel mechanism of action in targeting VASN, showing promise for HCC treatment alone or in combination therapy.

cancer biology↗

bioRxiv2018

Rapid Identification and Validation of Novel Rheumatoid Arthritis Drug Treatments using an Integrative Bioinformatics Platform

The majority of drugs currently used to treat rheumatoid arthritis (RA) act on a small number of immunomodulatory targets. We applied an integrative biomedical-informatics-based approach and in vivo testing to identify new drug candidates and potential therapeutic targets that could form the basis for future drug development in RA. A computational model of RA was constructed by integrating patient gene expression data, molecular interactions, and clinical drug-disease associations. Drug candidates were scored based on their predicted efficacy across these data types. Ten high-scoring candidates were subsequently screened in a collagen-induced arthritis model of RA. Treatment with exenatide, olopatadine, and TXR-112 significantly improved multiple preclinical endpoints, including animal mobility which was measured using a novel digital platform. These three drug candidates do not act on common RA therapeutic targets; however, links between known candidate pharmacology and pathological processes involved in RA suggest hypothetical mechanisms contributing to the observed efficacy.

bioinformatics↗

bioRxiv2017

5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages

5-Hydroxymethylcytosine (5hmC) is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC in circulating cell-free DNA (cfDNA) using a sensitive chemical labeling-based low-input shotgun sequencing approach. We sequenced cell-free 5hmC from 49 patients of seven different cancer types and found distinct features that could be used to predict cancer types and stages with high accuracy. Specifically, we discovered that lung cancer leads to a progressive global loss of 5hmC in cfDNA, whereas hepatocellular carcinoma and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our proof of principle results suggest that cell-free 5hmC signatures may potentially be used not only to identify cancer types but also to track tumor stage in some cancers.\n\nOne Sentence SummaryAnalyzing the epigenetic modification 5-hydroxymethylcysoine in circulating cell-free DNA reveals tumor tissue of origin and stages for cancer diagnostics.

genomics↗