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Potential use of RNA interference in cancer therapy

Published online by Cambridge University Press:  18 August 2010

Connor Phalon ,
Donald D. Rao  and
John Nemunaitis
Connor Phalon
Affiliation:
Gradalis, Inc., Dallas, TX, USA.
Donald D. Rao
Affiliation:
Gradalis, Inc., Dallas, TX, USA.
John Nemunaitis*
Affiliation:
Gradalis, Inc., Dallas, TX, USA. Mary Crowley Cancer Research Centers, Dallas, TX, USA. Texas Oncology PA, Dallas, TX, USA. Baylor Sammons Cancer Center, Dallas, TX, USA.
*
*Corresponding author: John Nemunaitis, 1700 Pacific Ave, Suite 1100, Dallas, TX 75201, USA. E-mail: jnemunaitis@marycrowley.org
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Abstract

RNA interference (RNAi) is an evolutionary conserved mechanism for specific gene silencing. This mechanism has great potential for use in targeted cancer therapy. Understanding the RNAi mechanism has led to the development of several novel RNAi-based therapeutic approaches currently in the early phases of clinical trials. It remains difficult to effectively deliver the nucleic acids required in vivo to initiate RNAi, and intense effort is under way in developing effective and targeted systemic delivery systems for RNAi. Description of in vivo delivery systems is not the focus of this review. In this review, we cover the rationale for pursuing personalised cancer therapy with RNAi, briefly review the mechanism of each major RNAi therapeutic technique, summarise and sample recent results with animal models applying RNAi for cancer, and provide an update on current clinical trials with RNAi-based therapeutic agents for cancer therapy. RNAi-based cancer therapy is still in its infancy, and there are numerous obstacles and issues that need to be resolved before its application in personalised therapy focusing on patient-cancer-specific targets can become standard cancer treatment, either alone or in combination with other treatments.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 12 , January 2010 , e26
Copyright
Copyright © Cambridge University Press 2010

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References

References

1Fire, A. et al. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806-811CrossRefGoogle ScholarPubMed
2Hannon, G.J. (2002) RNA interference. Nature 418, 244-251CrossRefGoogle ScholarPubMed
3Rao, D.D. et al. (2009) siRNA vs. shRNA: similarities and differences. Advanced Drug Delivery Reviews 61, 746-759CrossRefGoogle ScholarPubMed
4Kaklamani, V. and Gradishar, W. (2006) Gene expression in breast cancer. Current Treatment Options in Oncology 7, 123-128CrossRefGoogle ScholarPubMed
5Lu, J. et al. (2005) MicroRNA expression profiles classify human cancers. Nature 435, 834-838CrossRefGoogle ScholarPubMed
6Tong, A.W. and Nemunaitis, J. (2008) Modulation of miRNA activity in human cancer: a new paradigm for cancer gene therapy? Cancer Gene Therapy 15, 341-355CrossRefGoogle Scholar
7Wang, Y. et al. (2007) Gene expression profiles and prognostic markers for primary breast cancer. Methods in Molecular Biology 377, 131-138CrossRefGoogle ScholarPubMed
8Bild, A.H. et al. (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439, 353-357CrossRefGoogle ScholarPubMed
9Albert, R., Jeong, H. and Barabasi, A.-L. (2000) Error and attack tolerance of complex networks. Nature 406, 378-382CrossRefGoogle ScholarPubMed
10Weinstein, I.B. (2002) CANCER: enhanced: addiction to oncogenes–the Achilles heal of cancer. Science 297, 63-64CrossRefGoogle Scholar
11Nemunaitis, J. et al. (2007) Proof concept for clinical justification of network mapping for personalized cancer therapeutics. Cancer Gene Therapy 14, 686-695CrossRefGoogle ScholarPubMed
12Rao, D.D. et al. (2010) Enhanced target gene knockdown by a bifunctional shRNA: a novel approach of RNA interference. Cancer Gene Therapy Jul 2; [Epub ahead of print]CrossRefGoogle ScholarPubMed
13Fire, A. et al. (1991) Production of antisense RNA leads to effective and specific inhibition of gene expression in C. elegans muscle. Development 113, 503-514CrossRefGoogle ScholarPubMed
14Guo, S. and Kemphues, K.J. (1995) par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell 81, 611-620CrossRefGoogle Scholar
15Bernstein, E. et al. (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363-366CrossRefGoogle ScholarPubMed
16Ma, J.-B., Ye, K. and Patel, D.J. (2004) Structural basis for overhang-specific small interfering RNA recognition by the PAZ domain. Nature 429, 318-322CrossRefGoogle ScholarPubMed
17Zhang, H. et al. (2004) Single processing center models for human Dicer and bacterial RNase III. Cell 118, 57-68CrossRefGoogle ScholarPubMed
18Kok, K.H. et al. (2007) Human TRBP and PACT directly interact with each other and associate with Dicer to facilitate the production of small interfering RNA. Journal of Biological Chemistry 282, 17649-17657CrossRefGoogle ScholarPubMed
19Hammond, S.M. et al. (2000) An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 404, 293-296CrossRefGoogle ScholarPubMed
20Robb, G.B. and Rana, T.M. (2007) RNA helicase A interacts with RISC in human cells and functions in RISC loading. Molecular Cell 26, 523-537CrossRefGoogle ScholarPubMed
21Tomari, Y. et al. (2004) A protein sensor for siRNA asymmetry. Science 306, 1377-1380CrossRefGoogle ScholarPubMed
22Matranga, C. et al. (2005) Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 123, 607-620CrossRefGoogle ScholarPubMed
23Ma, J.B. et al. (2005) Structural basis for 5′-end-specific recognition of guide RNA by the A. Fulgidus Piwi protein. Nature 434, 666-670CrossRefGoogle ScholarPubMed
24Schwarz, D.S., Tomari, Y. and Zamore, P.D. (2004) The RNA-induced silencing complex is a Mg2+-dependent endonuclease. Current Biology 14, 787-791CrossRefGoogle ScholarPubMed
25Hammond, S.M. (2005) Dicing and slicing: the core machinery of the RNA interference pathway. FEBS Letters 579, 5822-5829CrossRefGoogle ScholarPubMed
26Gregory, R.I. et al. (2005) Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123, 631-640CrossRefGoogle ScholarPubMed
27Banan, M. and Puri, N. (2004) The ins and outs of RNAi in mammalian cells. Current Pharmaceutical Biotechnology 5, 441-450CrossRefGoogle ScholarPubMed
28Tang, G. (2005) siRNA and miRNA: an insight into RISCs. Trends in Biochemical Sciences 30, 106-114CrossRefGoogle ScholarPubMed
29Meister, G. and Tuschl, T. (2004) Mechanisms of gene silencing by double-stranded RNA. Nature 431, 343-349CrossRefGoogle ScholarPubMed
30Preall, J.B. and Sontheimer, E.J. (2005) RNAi: RISC gets loaded. Cell 123, 543-545CrossRefGoogle ScholarPubMed
31Sethupathy, P., Corda, B. and Hatzigeorgiou, A.G. (2006) TarBase: a comprehensive database of experimentally supported animal microRNA targets. RNA 12, 192-197CrossRefGoogle ScholarPubMed
32Meister, G. et al. (2004) Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Molecular Cell 15, 185-197CrossRefGoogle ScholarPubMed
33Pillai, R.S., Bhattacharyya, S.N. and Filipowicz, W. (2007) Repression of protein synthesis by miRNAs: how many mechanisms? Trends in Cell Biology 17, 118-126CrossRefGoogle ScholarPubMed
34Krek, A. et al. (2005) Combinatorial microRNA target predictions. Nature Genetics 37, 495-500CrossRefGoogle ScholarPubMed
35Cullen, B.R. (2005) RNAi the natural way. Nature Genetics 37, 1163-1165CrossRefGoogle ScholarPubMed
36Zeng, Y. and Cullen, B.R. (2006) Recognition and cleavage of primary microRNA transcripts. Methods in Molecular Biology 342, 49-56Google ScholarPubMed
37Lee, Y. et al. (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415-419CrossRefGoogle ScholarPubMed
38Yi, R. et al. (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes & Development 17, 3011-3016CrossRefGoogle ScholarPubMed
39Landthaler, M. et al. (2008) Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs. RNA 14, 2580-2596CrossRefGoogle ScholarPubMed
40Vorhies, J.S. and Nemunaitis, J. (2007) Nonviral delivery vehicles for use in short hairpin RNA-based cancer therapies. Expert Review of Anticancer Therapy 7, 373-382CrossRefGoogle ScholarPubMed
41Pardridge, W.M. (2007) shRNA and siRNA delivery to the brain. Advanced Drug Delivery Reviews 59, 141-152CrossRefGoogle ScholarPubMed
42Gondi, C.S. and Rao, J.S. (2009) Concepts in in vivo siRNA delivery for cancer therapy. Journal of Cellular Physiology 220, 285-291CrossRefGoogle ScholarPubMed
43Hughes, J.A. and Rao, G.A. (2005) Targeted polymers for gene delivery. Expert Opinion on Drug Delivery 2, 145CrossRefGoogle ScholarPubMed
44Devi, G.R. (2006) siRNA-based approaches in cancer therapy. Cancer Gene Therapy 13, 819-829CrossRefGoogle ScholarPubMed
45Wen, X. et al. (2009) Knockdown of p21-activated kinase 6 inhibits prostate cancer growth and enhances chemosensitivity to docetaxel. Urology 73, 1407-1411CrossRefGoogle ScholarPubMed
46Li, X. et al. (2008) Adenovirus-delivered CIAPIN1 small interfering RNA inhibits HCC growth in vitro and in vivo. Carcinogenesis 29, 1587-1593CrossRefGoogle ScholarPubMed
47Wang, J.S. et al. (2009) Gene silencing of beta-catenin by RNAi inhibits cell proliferation in human esophageal cancer cells in vitro and in nude mice. Diseases of the Esophagus 22, 151-162CrossRefGoogle ScholarPubMed
48He, X.W. et al. (2009) Vascular endothelial growth factor-C siRNA delivered via calcium carbonate nanoparticle effectively inhibits lymphangiogenesis and growth of colorectal cancer in vivo. Cancer Biotherapy & Radiopharmaceuticals 24, 249-259CrossRefGoogle ScholarPubMed
49Gong, M. et al. (2008) A small interfering RNA targeting osteopontin as gastric cancer therapeutics. Cancer Letters 272, 148-159CrossRefGoogle ScholarPubMed
50Zhang, X., Ge, Y.L. and Tian, R.H. (2009) The knockdown of c-myc expression by RNAi inhibits cell proliferation in human colon cancer HT-29 cells in vitro and in vivo. Cellular & Molecular Biology Letters 14, 305-318CrossRefGoogle ScholarPubMed
51Dong, K. et al. (2009) Tumor-specific RNAi targeting eIF4E suppresses tumor growth, induces apoptosis and enhances cisplatin cytotoxicity in human breast carcinoma cells. Breast Cancer Research and Treatment 113, 443-456CrossRefGoogle ScholarPubMed
52Wenqi, D. et al. (2009) EpCAM is overexpressed in gastric cancer and its downregulation suppresses proliferation of gastric cancer. Journal of Cancer Research and Clinical Oncology 135, 1277-1285CrossRefGoogle ScholarPubMed
53Zhou, H. et al. (2009) RNAi targeting urokinase-type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo. International Journal of Cancer 125, 453-462CrossRefGoogle ScholarPubMed
54Chen, T. and Deng, C. (2008) Inhibitory effect of siRNA targeting survivin in gastric cancer MGC-803 cells. International Immunopharmacology 8, 1006-1011CrossRefGoogle ScholarPubMed
55Zhang, X. et al. (2009) MicroRNA-17–3p is a prostate tumor suppressor in vitro and in vivo, and is decreased in high grade prostate tumors analyzed by laser capture microdissection. Clinical & Experimental Metastasis 26, 965-979CrossRefGoogle ScholarPubMed
56Mercatelli, N. et al. (2008) The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice. PLoS ONE 3, e4029CrossRefGoogle ScholarPubMed
57Li, J. et al. (2009) Silencing of signal transducer and activator of transcription 3 expression by RNA interference suppresses growth of human hepatocellular carcinoma in tumor-bearing nude mice. World Journal of Gastroenterology 15, 2602-2608CrossRefGoogle ScholarPubMed
58Schaefer, A. et al. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. International Journal of Cancer 126, 1166-1176CrossRefGoogle Scholar
59Takeshita, F. et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Molecular Therapy 18, 181-187CrossRefGoogle Scholar
60Kota, J. et al. (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137, 1005-1017CrossRefGoogle Scholar
61Zhang, W. et al. (2007) Expression of extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in pancreatic neoplasm and pancreatic stellate cells. Cancer Biology & Therapy 6, 218-227CrossRefGoogle ScholarPubMed
62Schneiderhan, W. et al. (2009) CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models. Gut 58, 1391-1398CrossRefGoogle ScholarPubMed
63Paragh, G. et al. (2009) RNA interference-mediated inhibition of erythropoietin receptor expression suppresses tumor growth and invasiveness in A2780 human ovarian carcinoma cells. American Journal of Pathology 174, 1504-1514CrossRefGoogle ScholarPubMed
64Davis, M.E. (2009) The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. Molecular Pharmaceutics 6, 659-668CrossRefGoogle Scholar
65Heidel, J.D. et al. (2007) Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo. Clinical Cancer Research 13, 2207-2215CrossRefGoogle ScholarPubMed
66Heidel, J.D. et al. (2007) Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA. Proceedings of the National Academy of Sciences of the United States of America 104, 5715-5721CrossRefGoogle ScholarPubMed
67Semple, S.C. et al. Rational design of cationic lipids for siRNA delivery. Nature Biotechnology 28, 172-176CrossRefGoogle Scholar
68Tao, W. et al. (2005) Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell 8, 49-59CrossRefGoogle ScholarPubMed
69Judge, A.D. et al. (2009) Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. Journal of Clinical Investigation 119, 661-673CrossRefGoogle ScholarPubMed
70Aleku, M. et al. (2008) Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Research 68, 9788-9798CrossRefGoogle ScholarPubMed
71Miyagishi, M. and Taira, K. (2002) Development and application of siRNA expression vector. Nucleic Acids Symposium Series (2004) 2, 113-114CrossRefGoogle Scholar
72Lopez-Fraga, M., Martinez, T. and Jimenez, A. (2009) RNA interference technologies and therapeutics: from basic research to products. BioDrugs 23, 305-332CrossRefGoogle ScholarPubMed
73Davis, M.E. et al. (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067-1070CrossRefGoogle ScholarPubMed
74Koldehoff, M. et al. (2007) Therapeutic application of small interfering RNA directed against bcr-abl transcripts to a patient with imatinib-resistant chronic myeloid leukaemia. Clinical and Experimental Medicine 7, 47-55CrossRefGoogle ScholarPubMed
75Maples, P.B. et al. (2010) FANG vaccine: autologous tumor vaccine genetically modified to express GM-CSF and block production of furin. BioProcessing Journal 8, 4-14CrossRefGoogle Scholar

Further reading, resources and contacts

Hannon, G.J. (2002) RNA interference. Nature 418, 244-251CrossRefGoogle ScholarPubMed
Bild, A.H. et al. (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439, 353-357CrossRefGoogle ScholarPubMed
Fire, A. et al. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806-811CrossRefGoogle ScholarPubMed
Devi, G.R. (2006) siRNA-based approaches in cancer therapy. Cancer Gene Therapy 13, 819-829CrossRefGoogle ScholarPubMed