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|Ref Type||Journal Article|
|Authors||Saadat N, Liu F, Haynes B, Nangia-Makker P, Bao X, Li J, Polin LA, Gupta S, Mao G, Shekhar MP|
|Title||Nano-delivery of RAD6/Translesion Synthesis Inhibitor SMI#9 for Triple-negative Breast Cancer Therapy.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||The triple-negative breast cancer (TNBC) subtype, regardless of their BRCA1 status, has the poorest outcome compared with other breast cancer subtypes, and currently there are no approved targeted therapies for TNBC. We have previously demonstrated the importance of RAD6-mediated translesion synthesis pathway in TNBC development/progression and chemoresistance, and the potential therapeutic benefit of targeting RAD6 with a RAD6-selective small-molecule inhibitor, SMI#9. To overcome SMI#9 solubility limitations, we recently developed a gold nanoparticle (GNP)-based platform for conjugation and intracellular release of SMI#9, and demonstrated its in vitro cytotoxic activity toward TNBC cells. Here, we characterized the in vivo pharmacokinetic and therapeutic properties of PEGylated GNP-conjugated SMI#9 in BRCA1 wild-type and BRCA1-mutant TNBC xenograft models, and investigated the impact of RAD6 inhibition on TNBC metabolism by 1H-NMR spectroscopy. GNP conjugation allowed the released SMI#9 to achieve higher systemic exposure and longer retention as compared with the unconjugated drug. Systemically administered SMI#9-GNP inhibited the TNBC growth as effectively as intratumorally injected unconjugated SMI#9. Inductively coupled mass spectrometry analysis showed highest GNP concentrations in tumors and liver of SMI#9-GNP and blank-GNP-treated mice; however, tumor growth inhibition occurred only in the SMI#9-GNP-treated group. SMI#9-GNP was tolerated without overt signs of toxicity. SMI#9-induced sensitization was associated with perturbation of a common set of glycolytic pathways in BRCA1 wild-type and BRCA1-mutant TNBC cells. These data reveal novel SMI#9 sensitive markers of metabolic vulnerability for TNBC management and suggest that nanotherapy-mediated RAD6 inhibition offers a promising strategy for TNBC treatment.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|SMI#9-GNP||SMI#9-GNP is comprised of the RAD6 inhibitor SMI#9 conjugated to gold nanoparticles (GNP), which potentially inhibits cell proliferation, colony formation, and tumor growth (PMID: 30242094).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||triple-receptor negative breast cancer||not applicable||SMI#9-GNP||Preclinical - Cell line xenograft||Actionable||In a preclinical study, SMI#9-GNP treatment inhibited proliferation, and colony formation, and induced apoptosis in triple-negative breast cancer cell lines harboring either wild-type or mutant BRCA1 in culture, and inhibited tumor growth in cell line xenograft models (PMID: 30242094).||30242094|