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Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):E3553-61. doi: 10.1073/pnas.1412686111. Epub 2014 Aug 11.

Small RNA combination therapy for lung cancer.

Author information

1
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Departments of Biology and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139;
2
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139;
3
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
4
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Departments of Biology and.
5
Tufts University and Harvard Medical School, Boston, MA 02115; and.
6
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
7
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
8
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139; Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
9
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139; Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; dgander@mit.edu tjacks@mit.edu.
10
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Departments of Biology and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139; dgander@mit.edu tjacks@mit.edu.

Abstract

MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.

KEYWORDS:

miR-34; nanotechnology

PMID:
25114235
PMCID:
PMC4151750
DOI:
10.1073/pnas.1412686111
[Indexed for MEDLINE]
Free PMC Article

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