Liver Cancer Research – Prof Patrick Arbuthnot
Prof Patrick Arbuthnot
- Personal Professor and Director: Antiviral Gene Therapy Research Unit, Department of Molecular Medicine & Haematology, University of the Witwatersrand
- E-mail: Patrick.Arbuthnot@wits.ac.za
Title of the Project
Signalling aptamers for the detection of HBV serological markers in patients at risk of hepatocellular carcinoma (project ended 31 March 2010)
Highlights of the Project
Countering the carcinogenic effects of chronic HBV infection is an important public health priority in South Africa. Development of RNA interference- (RNAi-) based silencing of the oncogenic HBx gene and also improved methods of identification of patients at risk for the malignancy has shown promise. With support of CANSA, significant progress has been made during the past 3 years and investigations are at an advanced stage of testing of efficacy in vivo in animal models. An important basis has been established that will enable advancing the technology to clinical application.
What has been achieved?
Hepatitis B virus (HBV) was one of the first viruses to be linked causally to a human tumour. Together with tobacco, it is now thought to be the most important environmental carcinogen to which humans are exposed. There are approximately 387 million carriers of HBV in the world today and as many as one-quarter of these will develop hepatocellular carcinoma (HCC). HBV is implicated in the aetiology of as much as 80% of the HCC that occurs with such high frequency in sub-Saharan African and Asian populations. Individuals who are chronic carriers have a greater than 100-fold increased relative risk for developing the tumour. Licensed treatments for HBV infection, which include IFN-α, nucleoside and nucleotide analogues, are limited by side effects, cost and variable efficacy. Although there is an efficient vaccine to prevent infection, vaccination is of little use to carriers of the virus. Problems related to persistent HBV infection are likely to continue for many years. Harnessing RNA interference (RNAi) to silence HBV genes specifically offers exciting possibilities for improvement of treatment. The focus of the previous and ongoing CANSA-supported research is use of engineered viruses (adenovirus vectors or Ads) to deliver anti HBV sequences to the liver. The cancer-causing HBx gene of the virus has been targeted and this approach has been found to be effective for inhibition of the infection. In addition to gene silencing, we are using new approacjhed to detect HBV carriers who are at risk for liver cancer. To do this, we are developing molecules that are capable of binding and measuring the concentration of the cancer-causing HBx protein in the serum of patients. The long term intended outcome of this research is development of innovative solutions to preventing a serious infection-related cancer of public health importance to South Africa.
How was this project of value in the struggle against cancer?
Chronic hepatitis B virus (HBV) infection is hyperendemic to southern Africa and is associated with a particularly high risk for hepatocellular carcinoma (HCC). Currently licensed HBV therapy has poor efficacy and the risk for liver cancer in treated individuals from South Africa is undiminished. HCC has a particularly poor prognosis and patients usually die within 2 months from the onset of symptoms related to the malignancy. The only effective means of treating HCC is through early detection when tumours are small and surgically resectable. Thus, development of effective treatment and methods of identifying HBV carriers at particularly high risk for HCC is an important medical objective. The research results obtained with support of CANSA indicate that use of RNAi to target HBx and silence HBV replication is a feasible approach to new treatment. The research is ongoing and our objectives are to refine the technology to enable clinical application.
Peer-reviewed Publications 2006 – 2009
- Ely, A., Naidoo, T. and Arbuthnot, P (2009) Efficient silencing of gene expression with modular trimeric Pol II expression cassettes comprising micro RNA shuttles, Nucleic Acids Research, In Press. (ISI Impact Factor 6.95)
- Liu, J., Ahiekpor, A., Li, L., Li, X., Arbuthnot, P., Kew, M. and Feitelson, M.A. (2009) Increased Expression of c-erbB-2 in Liver is Associated with Hepatitis B x Antigen and Shorter Survival in Patients with Liver Cancer, International Journal of Cancer, In Press. (ISI IF 4.6)
- Arbuthnot, P, Ely, A and Weinberg, MS (2009) Hepatic Delivery of RNA interference activators for therapeutic application, Current Gene Therapy, 9, 91-103 (ISI IF 4.45)
- Ely, A and Arbuthnot, P (2009) Advances in the use of RNA interference to treat chronic hepatitis B virus infection, In, RNAi and Viruses, Current Innovations and Future Trends Ed Martinez MA Horizon Scientific Press, UK, In Press (Book Chapter)
- Carmona, S, Jorgensen, MR, Kolli,S, Crowther, C, Salazar, FH, Marion, PL, Fujino, F, Natori, Y, Thanou, M, Arbuthnot, P and Miller, AD (2009) Controlling HBV Replication In vivo By Intravenous Administration of Triggered PEGylated siRNA-Nanoparticles, Molecular Pharmaceutics, In Press, (ISI IF 3.5)
- Islam, R U, Hean, J, van Otterlo, W A, de Koning, C B, Arbuthnot, P (2009) Efficient nucleic acid transduction with lipoplexes containing novel piperazine- and polyamine-conjugated cholesterol derivatives, Bioorg Med Chem Lett, 19, 100-3 (ISI IF 2.6)
- Weinberg MS and Arbuthnot P (2009) Gene Therapy, In, Molecular Medicine for Clinicians, Ed Mendelow B, Ramsay M, Chetty N, and Stevens W, Wits University Press, South Africa, ISBN, 978-1-86814-465-5, pp 413-421 (Book Chapter)
- Arbuthnot P and Weinberg MS (2009) Molecular research case study, Developing novel RNA Interference-based therapy, In, Molecular Medicine for Clinicians Ed Mendelow B, Ramsay M, Chetty N, and Stevens W, Wits University Press, South Africa, ISBN, 978-1-86814-465-5, pp441-448 (Book Chapter)
- Arbuthnot P (2009) Oncogenic Viruses, In, Molecular Medicine for Clinicians Ed Mendelow B, Ramsay M, Chetty N, and Stevens W, Wits University Press, South Africa, ISBN, 978-1-86814-465-5, pp359-366 (Book Chapter)
- Crowther, C, Ely, A, Hornby, J, Mufamadi, S, Salazar, F, Marion, P and Arbuthnot, P (2008) Efficient inhibition of hepatitis B virus replication in vivo using PEG-modified adenovirus vectors, Human Gene Therapy, 19, 1325-1331, (ISI IF 4.3)
- Kramvis, A, Arbuthnot, P, Swaby, L-A and Ukomadu, C (2008) Hepatitis B virus prevalence, natural history and treatment of Africans in Africa and the United States, Current Hepatitis B Reports, 2, 143–149, Current Medicine Group LLC
- Ely, A, Naidoo, T, Mufamadi S, Crowther, C and Arbuthnot, P (2008) Expressed anti-HBV primary microRNA shuttles inhibit viral replication efficiently in vitro and in vivo Molecular Therapy, 16(6), 1105-12, (ISI IF 5.862)
- Arbuthnot, P and Thompson, L (2008) Harnessing the RNA interference pathway to advance treatment and prevention of hepatocellular carcinoma World Journal of Gastroenterology, 14(11), 1670-1681
- Saayman, S, Barichievy, S, Capovilla, A, Morris, KV, Arbuthnot, P and Weinberg MS (2008) The Efficacy of Generating Three Independent Anti-HIV-1 siRNAs from a Single U6 RNA Pol III-Expressed Long Hairpin RNA, PLOS One, 3(7), e2602
- Barichievy, S, Saayman, S, Von Eije, KJ, Morris, KV, Arbuthnot, P and Weinberg MS (2007) The inhibitory efficacy of RNA POL III-expressed long hairpin RNAs targeted to untranslated regions of the HIV-1 5’ long terminal repeat Oligonucleotides, 17(4), 419-32 (ISI IF 3.143)
- Lian, Z, Liu, J, Wu, M, Wang, HY, Arbuthnot, P, Kew, MC and Feitelson MA (2007) Hepatitis B x antigen up-regulates vascular endothelial growth factor receptor 3 in hepatocarcinogenesis. Hepatology 45(6), 1390-9 (ISI IF 10.734)
- Weinberg, MS, Ely, A, Barichievy, S, Crowther, C, Mufamadi S, Carmona, S and Arbuthnot, P (2007) Specific Inhibition of HBV replication in vitro and in vivo with expressed long hairpin RNA, Molecular Therapy, 15(3), 534-41 (ISI IF 5.862)
- Arbuthnot, P, Longshaw V, Naidoo T and Weinberg, MS (2007). Opportunities for treating chronic hepatitis B and C virus infection using RNA interference,Journal of Viral Hepatitis, 14, 447-159 (ISI IF 2.97)
- Weinberg, MS, Ely, A, Passman, M, Mufamadi, SM and Arbuthnot, P (2007) Effective anti HBV hammerhead ribozymes derived from multimeric precursors, Oligonucleotides, 17, 104-112 (ISI IF 3.143)