Reference Detail

Ref Type

Journal Article

PMID

(30242094)

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	17	12	2018 12	2586-2597	Mol Cancer Ther

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
SMI#9-GNP	SMI#9-GNP	0	0

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