Pharmaceutical Research

, Volume 28, Issue 12, pp 2983–2995 | Cite as

RNA Interference and Cancer Therapy

  • Zhaohui Wang
  • Donald D. Rao
  • Neil Senzer
  • John Nemunaitis
Expert Review

ABSTRACT

Since its discovery in 1998, RNA interference (RNAi) has revolutionized basic and clinical research. Small RNAs, including small interfering RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA), mediate RNAi effects through either cleavage-dependent or cleavage-independent RNA inducible silencing complex (RISC) effector processes. As a result of its efficacy and potential, RNAi has been elevated to the status of “blockbuster therapeutic” alongside recombinant protein and monoclonal antibody. RNAi has already contributed to our understanding of neoplasia and has great promise for anti-cancer therapeutics, particularly so for personalized cancer therapy. Despite this potential, several hurdles have to be overcome for successful development of RNAi-based pharmaceuticals. This review will discuss the potential for, challenges to, and the current status of RNAi-based cancer therapeutics.

KEY WORDS

cancer therapy delivery RNA interference 

REFERENCES

  1. 1.
    Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–11.PubMedCrossRefGoogle Scholar
  2. 2.
    Lewis DL, Hagstrom JE, Loomis AG, Wolff JA, Herweijer H. Efficient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat Genet. 2002;32:107–8.PubMedCrossRefGoogle Scholar
  3. 3.
    McCaffrey AP, Meuse L, Pham TT, Conklin DS, Hannon GJ, Kay MA. RNA interference in adult mice. Nature. 2002;418:38–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Robb GB, Brown KM, Khurana J, Rana TM. Specific and potent RNAi in the nucleus of human cells. Nat Struct Mol Biol. 2005;12:133–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Lee NS, Dohjima T, Bauer G, Li H, Li MJ, Ehsani A, et al. Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol. 2002;20:500–5.PubMedGoogle Scholar
  7. 7.
    Yu JY, DeRuiter SL, Turner DL. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc Natl Acad Sci USA. 2002;99:6047–52.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Miyagishiand M, Taira K. U6 promoter-driven siRNAs with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cells. Nat Biotechnol. 2002;20:497–500.CrossRefGoogle Scholar
  9. 9.
    Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science. 2002;296:550–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Rao DD, Maples PB, Senzer N, Kumar P, Wang Z, Pappen BO, et al. Enhanced target gene knockdown by a bifunctional shRNA: a novel approach of RNA interference. Cancer Gene Ther. 2010;17:780–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Xia H, Mao Q, Paulson HL, Davidson BL. siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol. 2002;20:1006–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Rao DD, Vorhies JS, Senzer N, Nemunaitis J. siRNA vs. shRNA: similarities and differences. Adv Drug Deliv Rev. 2009;61:746–59.PubMedCrossRefGoogle Scholar
  13. 13.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.PubMedCrossRefGoogle Scholar
  14. 14.
    Liu J, Rivas FV, Wohlschlegel J, Yates 3rd JR, Parker R, Hannon GJ. A role for the P-body component GW182 in microRNA function. Nat Cell Biol. 2005;7:1261–6.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS. Human MicroRNA targets. PLoS Biol. 2004;2:e363.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet. 2008;40:43–50.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature. 2008;455:1124–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Lytle JR, Yario TA, Steitz JA. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci USA. 2007;104:9667–72.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Orom UA, Nielsen FC, Lund AH. MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell. 2008;30:460–71.PubMedCrossRefGoogle Scholar
  20. 20.
    Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA. 2008;105:1608–13.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Phadke AP, Jay CM, Wang Z, Chen S, Liu S, Haddock C, et al. In vivo Safety and Antitumor Efficacy of Bifunctional shRNAs Specific for the Human Stathmin 1 (STMN1) Oncoprotein. DNA Cell Biol. 2011;30(9):715–26.Google Scholar
  22. 22.
    Liu SH, Patel S, Gingras MC, Nemunaitis J, Zhou G, Chen C, et al. PDX-1: demonstration of oncogenic properties in pancreatic cancer. Cancer. 2011;117:723–33.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Liu S, Ballian N, Belaguli NS, Patel S, Li M, Templeton NS, et al. PDX-1 acts as a potential molecular target for treatment of human pancreatic cancer. Pancreas. 2008;37:210–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Minakuchi Y, Takeshita F, Kosaka N, Sasaki H, Yamamoto Y, Kouno M, et al. Atelocollagen-mediated synthetic small interfering RNA delivery for effective gene silencing in vitro and in vivo. Nucleic Acids Res. 2004;32:e109.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Ryo A, Uemura H, Ishiguro H, Saitoh T, Yamaguchi A, Perrem K, et al. Stable suppression of tumorigenicity by Pin1-targeted RNA interference in prostate cancer. Clin Cancer Res. 2005;11:7523–31.PubMedCrossRefGoogle Scholar
  26. 26.
    Takei Y, Kadomatsu K, Yuzawa Y, Matsuo S, Muramatsu T. A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res. 2004;64:3365–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G, et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 2004;32:e149.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, et al. RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res. 2008;68:7975–84.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Rana S, Maples PB, Senzer N, Nemunaitis J. Stathmin 1: a novel therapeutic target for anticancer activity. Expert Rev Anticancer Ther. 2008;8:1461–70.PubMedCrossRefGoogle Scholar
  30. 30.
    Xiaoand C, Rajewsky K. MicroRNA control in the immune system: basic principles. Cell. 2009;136:26–36.CrossRefGoogle Scholar
  31. 31.
    Ibanez-Ventoso C, Yang M, Guo S, Robins H, Padgett RW, Driscoll M. Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging Cell. 2006;5:235–46.PubMedCrossRefGoogle Scholar
  32. 32.
    Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 11:597–610.Google Scholar
  33. 33.
    Zhaoand Y, Srivastava D. A developmental view of microRNA function. Trends Biochem Sci. 2007;32:189–97.CrossRefGoogle Scholar
  34. 34.
    Lu M, Zhang Q, Deng M, Miao J, Guo Y, Gao W, et al. An analysis of human microRNA and disease associations. PLoS One. 2008;3:e3420.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med. 2009;361:1437–47.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Liu X, Sempere LF, Galimberti F, Freemantle SJ, Black C, Dragnev KH, et al. Uncovering growth-suppressive MicroRNAs in lung cancer. Clin Cancer Res. 2009;15:1177–83.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Trang P, Wiggins JF, Daige CL, Cho C, Omotola M, Brown D, et al. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol Ther. 2011;19:1116–22.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17:211–5.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Takeshita F, Patrawala L, Osaki M, Takahashi RU, Yamamoto Y, Kosaka N, et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther. 2010;18:181–7.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Xu D, Takeshita F, Hino Y, Fukunaga S, Kudo Y, Tamaki A, et al. miR-22 represses cancer progression by inducing cellular senescence. J Cell Biol. 2011;193:409–24.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009;137:1005–17.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Liu X, Sempere LF, Ouyang H, Memoli VA, Andrew AS, Luo Y, et al. MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors. J Clin Invest. 2010;120:1298–309.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 70:3119–27.Google Scholar
  44. 44.
    Ma L, Reinhardt F, Pan E, Soutschek J, Bhat B, Marcusson EG, et al. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat Biotechnol. 2010;28:341–7.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438:685–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009;324:1710–3.PubMedCrossRefGoogle Scholar
  47. 47.
    Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 2007;4:721–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Haraguchi T, Ozaki Y, Iba H. Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res. 2009;37:e43.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Choi WY, Giraldez AJ, Schier AF. Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430. Science. 2007;318:271–4.PubMedCrossRefGoogle Scholar
  50. 50.
    Xiao J, Yang B, Lin H, Lu Y, Luo X, Wang Z. Novel approaches for gene-specific interference via manipulating actions of microRNAs: examination on the pacemaker channel genes HCN2 and HCN4. J Cell Physiol. 2007;212:285–92.PubMedCrossRefGoogle Scholar
  51. 51.
    Gumireddy K, Young DD, Xiong X, Hogenesch JB, Huang Q, Deiters A. Small-molecule inhibitors of microrna miR-21 function. Angew Chem Int Ed Engl. 2008;47:7482–4.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Dannull J, Lesher DT, Holzknecht R, Qi W, Hanna G, Seigler H, et al. Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity. Blood. 2007;110:4341–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Shen L, Evel-Kabler K, Strube R, Chen SY. Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nat Biotechnol. 2004;22:1546–53.PubMedCrossRefGoogle Scholar
  54. 54.
    Song XT, Evel-Kabler K, Shen L, Rollins L, Huang XF, Chen SY. A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression. Nat Med. 2008;14:258–65.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9:1269–74.PubMedCrossRefGoogle Scholar
  56. 56.
    Zheng X, Koropatnick J, Li M, Zhang X, Ling F, Ren X, et al. Reinstalling antitumor immunity by inhibiting tumor-derived immunosuppressive molecule IDO through RNA interference. J Immunol. 2006;177:5639–46.PubMedGoogle Scholar
  57. 57.
    Poeck H, Besch R, Maihoefer C, Renn M, Tormo D, Morskaya SS, et al. 5′-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat Med. 2008;14:1256–63.PubMedCrossRefGoogle Scholar
  58. 58.
    Kortylewski M, Swiderski P, Herrmann A, Wang L, Kowolik C, Kujawski M, et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol. 2009;27:925–32.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Dominska M, Dykxhoorn DM. Breaking down the barriers: siRNA delivery and endosome escape. J Cell Sci. 2010;123:1183–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Brannon-Peppas L, Blanchette JO. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev. 2004;56:1649–59.PubMedCrossRefGoogle Scholar
  61. 61.
    Templeton NS, Lasic DD, Frederik PM, Strey HH, Roberts DD, Pavlakis GN. Improved DNA: liposome complexes for increased systemic delivery and gene expression. Nat Biotechnol. 1997;15:647–52.PubMedCrossRefGoogle Scholar
  62. 62.
    Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. 2010;464:1067–70.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Han HD, Mangala LS, Lee JW, Shahzad MM, Kim HS, Shen D, et al. Targeted gene silencing using RGD-labeled chitosan nanoparticles. Clin Cancer Res. 16:3910–22.Google Scholar
  64. 64.
    Shi Q, Nguyen AT, Angell Y, Deng D, Na CR, Burgess K, et al. A combinatorial approach for targeted delivery using small molecules and reversible masking to bypass nonspecific uptake in vivo. Gene Ther. 2010;17:1085–97.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Judge AD, Sood V, Shaw JR, Fang D, McClintock K, MacLachlan I. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol. 2005;23:457–62.PubMedCrossRefGoogle Scholar
  66. 66.
    Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med. 2005;11:263–70.PubMedCrossRefGoogle Scholar
  67. 67.
    Robbins M, Judge A, MacLachlan I. siRNA and innate immunity. Oligonucleotides. 2009;19:89–102.PubMedCrossRefGoogle Scholar
  68. 68.
    Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008;452:591–7.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Birmingham A, Anderson EM, Reynolds A, Ilsley-Tyree D, Leake D, Fedorov Y, et al. 3′ UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat Methods. 2006;3:199–204.PubMedCrossRefGoogle Scholar
  70. 70.
    Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M, Lim L, et al. Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA. 2006;12:1179–87.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Grimm D, Streetz KL, Jopling CL, Storm TA, Pandey K, Davis CR, et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature. 2006;441:537–41.PubMedCrossRefGoogle Scholar
  72. 72.
    McBride JL, Boudreau RL, Harper SQ, Staber PD, Monteys AM, Martins I, et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc Natl Acad Sci USA. 2008;105:5868–73.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    John M, Constien R, Akinc A, Goldberg M, Moon YA, Spranger M, et al. Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway. Nature. 2007;449:745–7.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Grimm D, Wang L, Lee JS, Schurmann N, Gu S, Borner K, et al. Argonaute proteins are key determinants of RNAi efficacy, toxicity, and persistence in the adult mouse liver. J Clin Invest. 120:3106–19.Google Scholar
  75. 75.
    Giering JC, Grimm D, Storm TA, Kay MA. Expression of shRNA from a tissue-specific pol II promoter is an effective and safe RNAi therapeutic. Mol Ther. 2008;16:1630–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Tremblay GA, Oldfield PR. Bioanalysis of siRNA and oligonucleotide therapeutics in biological fluids and tissues. Bioanalysis. 2009;1:595–609.PubMedCrossRefGoogle Scholar
  77. 77.
    Cervantes A, Alsina M, Tabernero J, Infante JR, LoRusso P, Shapiro G, et al. Phase I dose-escalation study of ALN-VSP02, a novel RNAi therapeutic for solid tumors with liver involvement. J Clin Oncol. 2011;29.Google Scholar
  78. 78.
    Abrams MT, Koser ML, Seitzer J, Williams SC, DiPietro MA, Wang W, et al. Evaluation of efficacy, biodistribution, and inflammation for a potent siRNA nanoparticle: effect of dexamethasone co-treatment. Mol Ther. 2010;18:171–80.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Seitzer J, Zhang H, Koser M, Pei Y, Abrams M. Effect of biological matrix and sample preparation on qPCR quantitation of siRNA drugs in animal tissues. J Pharmacol Toxicol Methods. 2011;63:168–73.PubMedCrossRefGoogle Scholar
  80. 80.
    Landesman Y, Svrzikapa N, Cognetta 3rd A, Zhang X, Bettencourt BR, Kuchimanchi S, et al. In vivo quantification of formulated and chemically modified small interfering RNA by heating-in-Triton quantitative reverse transcription polymerase chain reaction (HIT qRT-PCR). Silence. 2010;1:16.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005;33:e179.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 2004;432:173–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, et al. RNAi-mediated gene silencing in non-human primates. Nature. 2006;441:111–4.PubMedCrossRefGoogle Scholar
  84. 84.
    Santel A, Aleku M, Roder N, Mopert K, Durieux B, Janke O, et al. Atu027 prevents pulmonary metastasis in experimental and spontaneous mouse metastasis models. Clin Cancer Res. 2010;16:5469–80.PubMedCrossRefGoogle Scholar
  85. 85.
    Patnaik A, Chiorean EG, Tolcher A, Papadopoulos K, Beeram M, Kee D, et al. EZN-2968, a novel hypoxia-inducible factor-1α (HIF-1α) messenger ribonucleic acid (mRNA) antagonist: Results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies. J Clin Oncol. 2009;27:15s (suppl; abstr 2564).CrossRefGoogle Scholar
  86. 86.
    Maples PB, Kumar P, Yu Y, Wang Z, Jay CM, Pappen BO, et al. FANG vaccine: autologous tumor vaccine genetically modified to express GM-CSF and block production of furin. Bioprocess J. 2010;8:4–14.Google Scholar
  87. 87.
    Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R. Processing of transforming growth factor beta 1 precursor by human furin convertase. J Biol Chem. 1995;270:10618–24.PubMedCrossRefGoogle Scholar
  88. 88.
    Blanchette F, Day R, Dong W, Laprise MH, Dubois CM. TGFbeta1 regulates gene expression of its own converting enzyme furin. J Clin Invest. 1997;99:1974–83.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, et al. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature. 2008;455:246–50.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Rolle K, Nowak S, Wyszko E, Nowak M, Zukiel R, Piestrzeniewicz R, et al. Promising human brain tumors therapy with interference RNA intervention (iRNAi). Cancer Biol Ther. 2010;9:396–406.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Zhaohui Wang
    • 1
  • Donald D. Rao
    • 1
  • Neil Senzer
    • 1
    • 2
    • 3
    • 4
  • John Nemunaitis
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.Gradalis, Inc.DallasUSA
  2. 2.Mary Crowley Cancer Research CentersDallasUSA
  3. 3.Texas Oncology PADallasUSA
  4. 4.Medical City Dallas HospitalDallasUSA
  5. 5.DallasUSA

Personalised recommendations