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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.

Author information

1
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
2
Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
3
DLVR Therapeutics Inc. and University Health Network, Toronto, Canada.
4
Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan.
5
Department of Pathology, NTT East Japan Sapporo Hospital, Sapporo, Hokkaido Japan.
6
Department of Thoracic Surgery, Sapporo Minami-Sanjo Hospital, Sapporo, Hokkaido, Japan.
7
Department of Medical Biophysics, University of Toronto, Toronto, Canada.
8
Institute of Biomaterials & Biomedical Engineering, University of Toronto, Toronto, Canada.
9
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. kazuhiro.yasufuku@uhn.ca.

Abstract

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.

PMID:
28993508
DOI:
10.1158/1541-7786.MCR-16-0341
[Indexed for MEDLINE]
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