title: Small RNA combination therapy for lung cancer.
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.
authors.affiliation: 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;
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.affiliation: 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;
authors.forename: James E
authors.initials: JE
authors.lastname: Dahlman
authors.affiliation: 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;
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Omar F
authors.initials: OF
authors.lastname: Khan
authors.affiliation: 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;
authors.forename: Sabina
authors.initials: S
authors.lastname: Sood
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Departments of Biology and.
authors.forename: Apeksha
authors.initials: A
authors.lastname: Dave
authors.affiliation: 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;
authors.forename: Wenxin
authors.initials: W
authors.lastname: Cai
authors.affiliation: 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;
authors.forename: Leilani M
authors.initials: LM
authors.lastname: Chirino
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Departments of Biology and.
authors.forename: Gillian R
authors.initials: GR
authors.lastname: Yang
authors.affiliation: Tufts University and Harvard Medical School, Boston, MA 02115; and.
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.affiliation: 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;
authors.forename: Denise G
authors.initials: DG
authors.lastname: Crowley
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sahay
authors.affiliation: 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.
authors.forename: Avi
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: 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;
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: 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.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: 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.
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D009154:Mutation; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use; D036103:Nanotechnology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002945:Cisplatin
keywords: miR-34; nanotechnology
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