Team:CSU CHINA/Description
Description
It's our honor to show our plan of gene therapy targeting liver cancer cells. Hepatocellular carcinoma (HCC) , the fifth most common cancer in the world and the N0.3 common cause of cancer-related mortality, posing potential and probable threat to public health significantly[1]. The mortality of Hepatitis in US surpasses that of AIDS, while China accounts for more than half of the world's new cases of liver cancer and death. We hope to provide a referential idea to help patients suffering from liver cancer out of pain in the future.
It is a treatment that artificially enhances or inhibits the immune function of the body to achieve the purpose of treating diseases by pointing to an immune state in which the body is lowered or hyperactive[2-5]. Unlike the previous methods, while immunotherapy targets are the body's own immune system, the emerging treatment aims at tumor cells and tissues[6-8]. Such as the well-known PD-L1(programmed death ligand 1) ,PD-1(programmed death 1), CTLA-4(cytotoxic T lymphocyte-associated antigen-4), anti-PD-1/PD-L1 and anti- CTLA-4 agents in cancer therapy[9-12], which are the hot topics definitely for Nobel Prize in Physiology or Medicine 2018[13-19].
HSV-TK/GCV is one of the popular methods.
GCV(ganciclovir) is a drug used for antiviral infection, which is harmless without TK(thymidine kinase) in normal cells. TK expressed by HSV-TK gene can phosphorylate GCV into GCV-TP, which becomes the competitive inhibitor in DNA synthesis and causes cell death by inducing apoptosis mechanisms.
The HSV-TK/GCV system mediates the irreparable double-stranded DNA break in cytotoxicity, and the homologous repair of the suppressor gene can significantly enhance the cytotoxicity of the HSVTK/GCV system[20]. The HSV-TK/GCV system has been shown to have good anti-tumor effects and is widely used in the treatment of various tumors.
This is a kind of therapy in which cellular material is injected into a patient, such as Cell vaccine and Stem cell transplantation, which is not covered in our design.
The main goal of us is to develop a sensitive genetic circuits system, to kill liver cancer cells specifically with the help of immunotherapy or Gene therapy as mentioned formerly.
GAL-4 is a yeast transcription factor that binds to UAS (upstream activating sequence) and activates transcription of linked genes. To make the transaction much stronger, we replace the activation domain(AD) of GAL-4 with VP-16[21].
When activited by liver cancer cells-specific promoters, GAL4-VP16 in turn drives the expression of effect element like HSV-thymidine kinase (HSV-TK) by binding to nine tandem UAS elements(to enhance the effect) in the promoter[22].
GAL-80, a GAL-4 inhibitor[23]. The high level of miRNA binding with the miRNA binding domain designed beforehand with liver cancer cells specificity could restrain the translation of GAL-80 in liver cancer cells. We design this part to ensure the system to be sensitive with liver cancer cells. Without the suppression of GAL-80, GAL4-VP16 could work as the transcription factor efficiently. Otherwise, the deficiency of miRNA in other cells cannot repress GAL-80[24].
As for the response element in the downstream for UAS, to achieve the function as tumor killer in the last step, we could appeal to HSV-TK/GCV or anti-PD-1/PD-L1 , producing the cell-killing drug in the liver cancer cells[25].
[1] Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of Liver Diseases in the World. J Hepatol. 2018
[2] Najafi M, Farhood B, Mortezaee K. Contribution of regulatory T cells to cancer: A review. J Cell Physiol. 2018
[3] Sharabi A, Tsokos MG, Ding Y, Malek TR, Klatzmann D, Tsokos GC. Regulatory T cells in the treatment of disease. Nat Rev Drug Discov. 2018
[4] Matosevic S. Viral and Nonviral Engineering of Natural Killer Cells as Emerging Adoptive Cancer Immunotherapies. J Immunol Res. 2018
[5] Liu P, Chen L, Zhang H. Natural Killer Cells in Liver Disease and Hepatocellular Carcinoma and the NK Cell-Based Immunotherapy. J Immunol Res. 2018
[6] Yu Y, Cui J. Present and future of cancer immunotherapy: A tumor microenvironmental perspective. Oncol Lett. 2018;16(4):4105-4113
[7] Marshall HT, Djamgoz MBA. Immuno-Oncology: Emerging Targets and Combination Therapies. Front Oncol. 2018
[8] Shevchenko I, Bazhin AV. Metabolic Checkpoints: Novel Avenues for Immunotherapy of Cancer. Front Immunol. 2018
[9] Kim N, Kim HS. Targeting Checkpoint Receptors and Molecules for Therapeutic Modulation of Natural Killer Cells. Front Immunol. 2018
[10] Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov. 2018;8(9):1069-1086
[11] Zhang J, Dang F, Ren J, Wei W. Biochemical Aspects of PD-L1 Regulation in Cancer Immunotherapy. Trends Biochem Sci. 2018
[12] Xu X, Tao Y, Shan L, et al. The Role of MicroRNAs in Hepatocellular Carcinoma. J Cancer. 2018;9(19):3557-3569
[13] Ishida, Y., Agata, Y., Shibahara, K., & Honjo, T. (1992). Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J., 11(11), 3887–3895
[14] Leach, D. R., Krummel, M. F., & Allison, J. P. (1996). Enhancement of antitumor immunity by CTLA-4 blockade. Science, 271(5256), 1734–1736.
[15] Kwon, E. D., Hurwitz, A. A., Foster, B. A., Madias, C., Feldhaus, A. L., Greenberg, N. M., Burg, M.B. & Allison, J.P. (1997). Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci USA, 94(15), 8099–8103
[16] Nishimura, H., Nose, M., Hiai, H., Minato, N., & Honjo, T. (1999). Development of Lupus-like Autoimmune Diseases by Disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 11, 141–151
[17] Freeman, G.J., Long, A.J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L.J., Malenkovich, N., Okazaki, T., Byrne, M.C., Horton, H.F., Fouser, L., Carter, L., Ling, V., Bowman, M.R., Carreno, B.M., Collins, M., Wood, C.R. & Honjo, T. (2000). Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med, 192(7), 1027–1034
[18] Hodi, F.S., Mihm, M.C., Soiffer, R.J., Haluska, F.G., Butler, M., Seiden, M.V., Davis, T., Henry-Spires, R., MacRae, S., Willman, A., Padera, R., Jaklitsch, M.T., Shankar, S., Chen, T.C., Korman, A., Allison, J.P. & Dranoff, G. (2003). Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA, 100(8), 4712-4717
[19] Iwai, Y., Terawaki, S., & Honjo, T. (2005). PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol, 17(2), 133–144
[20] Zhang Q, Liu Z, Hou J, et al. Improved safety of a replication-competent poxvirus-based HIV vaccine with the introduction of the HSV-TK/GCV suicide gene system. Vaccine. 2016;34(30):3447-53
[21] Sadowski I, Ma J, Triezenberg S, Ptashne M. GAL4-VP16 is an unusually potent transcriptional activator. Nature. 1988;335(6190):563-4
[22] Elliott DA, Brand AH. The GAL4 system : a versatile system for the expression of genes. Methods Mol Biol. 2008
[23] Lohr D, Venkov P, Zlatanova J. Transcriptional regulation in the yeast GAL gene family: a complex genetic network. FASEB J. 1995;9(9):777-87
[24] Johnston M. A model fungal gene regulatory mechanism: the GAL genes of Saccharomyces cerevisiae. Microbiol Rev. 1987;51(4):458-76
[25] Xu F, Jin T, Zhu Y, Dai C. Immune checkpoint therapy in liver cancer. J Exp Clin Cancer Res. 2018;37(1):110
