RNA Activation pp 189-194 | Cite as

Treatment of Liver Cancer by C/EBPA saRNA

  • Xiaoyang Zhao
  • Jon Voutila
  • Stephanos Ghobrial
  • Nagy A. Habib
  • Vikash Reebye
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 983)

Abstract

The prognosis for hepatocellular carcinoma (HCC) remains poor and has not improved in over two decades. Most patients with advanced HCC who are not eligible for surgery have limited treatment options due to poor liver function or large, unresectable tumors. Although sorafenib is the standard-of-care treatment for these patients, only a small number respond. For the remaining, the outlook remains bleak. A better approach to target “undruggable” molecular pathways that reverse HCC is therefore urgently needed. Small activating RNAs (saRNAs) may provide a novel strategy to activate expression of genes that become dysregulated in chronic disease. The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα), a critical regulator of hepatocyte function, is suppressed in many advanced liver diseases. By using an saRNA to activate C/EBPα, we can exploit the cell’s own transcription machinery to enhance gene expression without relying on exogenous vectors that have been the backbone of gene therapy. saRNAs do not integrate into the host genome and can be modified to avoid immune stimulation. In preclinical models of liver disease, treatment with C/EBPα saRNA has shown reduction in tumor volume and improvement in serum markers of essential liver function such as albumin, bilirubin, aspartate aminotransferase (AST), and alanine transaminase (ALT). This saRNA that activates C/EBPα for advanced HCC is the first saRNA therapy to have entered a human clinical trial. The hope is that this new tool will help break the dismal 20-year trend and provide a more positive prognosis for patients with severe liver disease.

Keywords

Oligonucleotide therapy Small activating RNA Hepatocellular carcinoma CEBPA transcription factor Liver disease 

References

  1. 1.
    Belghiti J, Panis Y, Farges O, Benhamou JP, Fekete F (1991) Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg 214(2):114–117CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bray F, Jemal A, Grey N, Ferlay J, Forman D (2012) Global cancer transitions according to the Human Development Index (2008–2030): a population-based study. Lancet Oncol 13(8):790–801. doi:10.1016/S1470-2045(12)70211-5 CrossRefPubMedGoogle Scholar
  3. 3.
    Choi KJ, Baik IH, Ye SK, Lee YH (2015) Molecular targeted therapy for hepatocellular carcinoma: present status and future directions. Biol Pharm Bull 38(7):986–991. doi:10.1248/bpb.b15-00231 CrossRefPubMedGoogle Scholar
  4. 4.
    Chuma M, Terashita K, Sakamoto N (2015) New molecularly targeted therapies against advanced hepatocellular carcinoma: from molecular pathogenesis to clinical trials and future directions. Hepatol Res 45(10):E1–E11. doi:10.1111/hepr.12459 CrossRefPubMedGoogle Scholar
  5. 5.
    ClinicalTrials.gov (2016) First-in-human safety and tolerability study of MTL-CEBPA in patients with advanced liver cancer. https://ClinicalTrials.gov/show/NCT02716012
  6. 6.
    Flodby P, Liao DZ, Blanck A, Xanthopoulos KG, Hallstrom IP (1995) Expression of the liver-enriched transcription factors C/EBP alpha, C/EBP beta, HNF-1, and HNF-4 in preneoplastic nodules and hepatocellular carcinoma in rat liver. Mol Carcinog 12(2):103–109CrossRefPubMedGoogle Scholar
  7. 7.
    Johnson PJ (2005) Non-surgical treatment of hepatocellular carcinoma. HPB (Oxford) 7(1):50–55. doi:10.1080/13651820410024076 CrossRefGoogle Scholar
  8. 8.
    Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, O’Beirne J, Fox R, Skowronska A, Palmer D, Yeo W, Mo F, Lai P, Inarrairaegui M, Chan SL, Sangro B, Miksad R, Tada T, Kumada T, Toyoda H (2015) Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol 33(6):550–558. doi:10.1200/JCO.2014.57.9151 CrossRefPubMedGoogle Scholar
  9. 9.
    Matsusue K, Gavrilova O, Lambert G, Brewer HB Jr, Ward JM, Inoue Y, LeRoith D, Gonzalez FJ (2004) Hepatic CCAAT/enhancer binding protein alpha mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice. Mol Endocrinol 18(11):2751–2764. doi:10.1210/me.2004-0213 CrossRefPubMedGoogle Scholar
  10. 10.
    McKnight SL (2001) McBindall—a better name for CCAAT/enhancer binding proteins? Cell 107(3):259–261CrossRefPubMedGoogle Scholar
  11. 11.
    Mei S, Wang X, Zhang J, Qian J, Ji J (2007) In vivo transfection of C/EBP-alpha gene could ameliorate CCL(4)-induced hepatic fibrosis in mice. Hepatol Res 37(7):531–539. doi:10.1111/j.1872-034X.2007.00074.x CrossRefPubMedGoogle Scholar
  12. 12.
    Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J, Murray CJ, Naghavi M (2014) Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med 12:145. doi:10.1186/s12916-014-0145-y CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Nagasue N, Uchida M, Makino Y, Takemoto Y, Yamanoi A, Hayashi T, Chang YC, Kohno H, Nakamura T, Yukaya H (1993) Incidence and factors associated with intrahepatic recurrence following resection of hepatocellular carcinoma. Gastroenterology 105(2):488–494CrossRefPubMedGoogle Scholar
  14. 14.
    Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP (2006) The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 45(4):529–538. doi:10.1016/j.jhep.2006.05.013 CrossRefPubMedGoogle Scholar
  15. 15.
    Ramji DP, Foka P (2002) CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J 365(Pt 3):561–575. doi:10.1042/BJ20020508 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Reebye V, Saetrom P, Mintz PJ, Huang KW, Swiderski P, Peng L, Liu C, Liu X, Lindkaer-Jensen S, Zacharoulis D, Kostomitsopoulos N, Kasahara N, Nicholls JP, Jiao LR, Pai M, Spalding DR, Mizandari M, Chikovani T, Emara MM, Haoudi A, Tomalia DA, Rossi JJ, Habib NA (2014) Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. Hepatology 59(1):216–227. doi:10.1002/hep.26669 CrossRefPubMedGoogle Scholar
  17. 17.
    Reebye V, Voutila J, Huang KW, Muragundla A, Jayaprakash A, Vadnal P, Huber H, Habib R, Saetrom P, Rossi J, Habib N (2015) Systemic administration of a novel development candidate, MTL-CEBPA, up-regulates the liver-enriched transcription factor C/EBP-alpha and reverses CCl4-induced liver failure in vivo. Hepatology 62:269a–270aGoogle Scholar
  18. 18.
    Schmidt S, Follmann M, Malek N, Manns MP, Greten TF (2011) Critical appraisal of clinical practice guidelines for diagnosis and treatment of hepatocellular carcinoma. J Gastroenterol Hepatol 26(12):1779–1786. doi:10.1111/j.1440-1746.2011.06891.x CrossRefPubMedGoogle Scholar
  19. 19.
    Schuster MB, Porse BT (2006) C/EBPalpha: a tumour suppressor in multiple tissues? Biochim Biophys Acta 1766(1):88–103. doi:10.1016/j.bbcan.2006.02.003 PubMedGoogle Scholar
  20. 20.
    Simonetti RG, Camma C, Fiorello F, Politi F, D’Amico G, Pagliaro L (1991) Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci 36(7):962–972CrossRefPubMedGoogle Scholar
  21. 21.
    Soriano HE, Kang DC, Finegold MJ, Hicks MJ, Wang ND, Harrison W, Darlington GJ (1998) Lack of C/EBP alpha gene expression results in increased DNA synthesis and an increased frequency of immortalization of freshly isolated mice [correction of rat] hepatocytes. Hepatology 27(2):392–401. doi:10.1002/hep.510270212 CrossRefPubMedGoogle Scholar
  22. 22.
    Stewart BW, Wild C, International Agency for Research on Cancer, World Health Organization (2014) World cancer report 2014. International Agency for Research on Cancer. WHO Press, Lyon/GenevaGoogle Scholar
  23. 23.
    Tan EH, Hooi SC, Laban M, Wong E, Ponniah S, Wee A, Wang ND (2005) CCAAT/enhancer binding protein alpha knock-in mice exhibit early liver glycogen storage and reduced susceptibility to hepatocellular carcinoma. Cancer Res 65(22):10330–10337. doi:10.1158/0008-5472.CAN-04-4486 CrossRefPubMedGoogle Scholar
  24. 24.
    Tao LL, Cheng YY, Ding D, Mei S, Xu JW, Yu J, Ou-Yang Q, Deng L, Chen Q, Li QQ, Xu ZD, Liu XP (2012) C/EBP-alpha ameliorates CCl(4)-induced liver fibrosis in mice through promoting apoptosis of hepatic stellate cells with little apoptotic effect on hepatocytes in vitro and in vivo. Apoptosis 17(5):492–502. doi:10.1007/s10495-012-0700-y CrossRefPubMedGoogle Scholar
  25. 25.
    Tseng HH, Hwang YH, Yeh KT, Chang JG, Chen YL, Yu HS (2009) Reduced expression of C/EBP alpha protein in hepatocellular carcinoma is associated with advanced tumor stage and shortened patient survival. J Cancer Res Clin Oncol 135(2):241–247. doi:10.1007/s00432-008-0448-5 CrossRefPubMedGoogle Scholar
  26. 26.
    Voutila J, Reebye V, Roberts T, Blakey D, Habib R, Huber H, Saetrom P, Rossi JJ, Habib NA (2016) Development and mechanism of a small activating RNA targeting CEBPA, a novel therapeutic in clinical trials for patients with liver cancer. Poster presented at the The Oligo meeting, Montreal, CanadaGoogle Scholar
  27. 27.
    Zhou J, Neff CP, Liu X, Zhang J, Li H, Smith DD, Swiderski P, Aboellail T, Huang Y, Du Q, Liang Z, Peng L, Akkina R, Rossi JJ (2011) Systemic administration of combinatorial dsiRNAs via nanoparticles efficiently suppresses HIV-1 infection in humanized mice. Mol Ther 19(12):2228–2238. doi:10.1038/mt.2011.207 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Xiaoyang Zhao
    • 1
  • Jon Voutila
    • 2
  • Stephanos Ghobrial
    • 1
  • Nagy A. Habib
    • 1
  • Vikash Reebye
    • 1
  1. 1.Department of Surgery, Hammersmith HospitalImperial College LondonLondonUK
  2. 2.MiNA Therapeutics Ltd.LondonUK

Personalised recommendations