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Mol Cancer Res. 2018 Jan;16(1):47-57. doi: 10.1158/1541-7786.MCR-16-0341. Epub 2017 Oct 9.

Personalized siRNA-Nanoparticle Systemic Therapy using Metastatic Lymph Node Specimens Obtained with EBUS-TBNA in Lung Cancer.

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Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
DLVR Therapeutics Inc. and University Health Network, Toronto, Canada.
Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan.
Department of Pathology, NTT East Japan Sapporo Hospital, Sapporo, Hokkaido Japan.
Department of Thoracic Surgery, Sapporo Minami-Sanjo Hospital, Sapporo, Hokkaido, Japan.
Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Institute of Biomaterials & Biomedical Engineering, University of Toronto, Toronto, Canada.
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.


Inhibiting specific gene expression with siRNA provides a new therapeutic strategy to tackle many diseases at the molecular level. Recent strategies called high-density lipoprotein (HDL)-mimicking peptide-phospholipid nanoscaffold (HPPS) nanoparticles have been used to induce siRNAs-targeted delivery to scavenger receptor class B type I receptor (SCARB1)-expressing cancer cells with high efficiency. Here, eight ideal therapeutic target genes were identified for advanced lung cancer throughout the screenings using endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA) and the establishment of a personalized siRNA-nanoparticle therapy. The relevance of these genes was evaluated by means of siRNA experiments in cancer cell growth. To establish a therapeutic model, kinesin family member-11 (KIF11) was selected as a target gene. A total of 356 lung cancers were analyzed immunohistochemically for its clinicopathologic significance. The antitumor effect of HPPS-conjugated siRNA was evaluated in vivo using xenograft tumor models. Inhibition of gene expression for these targets effectively suppressed lung cancer cell growth. SCARB1 was highly expressed in a subset of tumors from the lung large-cell carcinoma (LCC) and small-cell lung cancer (SCLC) patients. High-level KIF11 expression was identified as an independent prognostic factor in LCC and squamous cell carcinoma (SqCC) patients. Finally, a conjugate of siRNA against KIF11 and HPPS nanoparticles induced downregulation of KIF11 expression and mediated dramatic inhibition of tumor growth in vivoImplications: This approach showed delivering personalized cancer-specific siRNAs via the appropriate nanocarrier may be a novel therapeutic option for patients with advanced lung cancer. Mol Cancer Res; 16(1); 47-57. ©2017 AACR.

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