The Cancer Gene therapy group specializes in development of clinically translatable methods for cancer treatment based on gene therapy vectors and combination of different strategies including chemotherapy and immunotherapy. The group uses a wide variety of alphaviral vectors as promising candidates for transient intratumoral delivery of therapeutic genes. Being recently established the group has generated a strong collaborative network with experts in complementary fields: chemists, bioinformatics, immunologists. Currently, the group leads two collaborative projects focused on delivery of alphaviral RNA into tumor, using classical way through infection with recombinant virus (i) and alternative way through viral RNA delivery by magnetic nanoparticles and polyfunctional pyridinium amphiphiles (ii). Moreover, the group has a strong interest in unraveling fine mechanisms of alphavirus infection and identification of factors of tumor microenvironment for efficient targeting of cancer cells.
Tumor-associate macrophages (TAM) constitute a key regulatory component of tumor microenvironment. The most advanced approach to instruct macrophages to stop supporting tumor progression and to act against tumor is their functional reprogramming. Therefore, we are focusing our efforts on delivery of cytokine genes to induce polarization of TAM into pro-inflammatory tumour suppressive M1 phenotype.
Combined therapy is a good platform for clinical application. In that context, alphaviral vectors possess a significant potential to be translated into clinics as adjuvant/neoadjuvant treatment to block tumor recovery after chemotherapy. We continue pre-clinical evaluation of alphaviral vectors in combination with standard and advanced chemotherapeutics in order to find the optimal treatment strategy (i), to overcome drug resistance (ii) and to understand the mechanism of possible synergistic effects (iii).
The mechanism of alphavirus infection and possible regulation of entry, which is important for tumor targeting, is currently controversial. We have analysed the full proteome of mouse melanoma cells susceptible and unsusceptible to alphavirus infection. The identified genes and pathways potentially could serve as a platform for regulation of tumor environment to facilitate virus tumor targeting. On the other hand, to enhance the efficiency of the delivery and transgene production in tumor, we propose to apply re-administration strategy using non-viral delivery of alphaviral RNA. This approach will help to overcome the anti-vector immune response caused by virus administration. To deliver alphaviral RNA we use targeted liposomes and magnetic nano-particles with attached oligonucleotides complementary to RNA. Fluorescent dyes will be used to track particle distribution in vivo. Moreover, magnetic nanoparticles adsorbed on the surface of the virus will be tested for the ability to address virus to tumor sites with higher efficiency by magnetic field.
1. Zajakina A, Spunde K and Lundstrom K. Application of alphaviral vectors for immunomodulation in cancer therapy. Curr Pharm Des. Accepted for publication.
2. Vasilevska J, De Souza G A, Stensland M, Skrastina D, Zhulenkovs D, Paplausks R, Kurena B, Kozlovska T, Zajakina A. Comparative protein profiling of B16 mouse melanoma cells susceptible and non-susceptible to alphavirus infection: effect of the tumor microenvironment. Cancer Biol Ther. 2016 Aug 11:1-16.
3. Zajakina A, Vasilevska J, Kozlovska T, Lundstrom K. Alphaviral Vectors for Cancer Treatment. Viral Nanotechnology. CRC Press, Taylor & Francis Group. 2015. Chapter 28, 467-485.
4. Zajakina A, J. Vasilevska, D. Zhulenkov, A. Spaks, A. Plotniece, T. Kozlovska. High efficiency of alphaviral gene transfer in combination with 5-fluorouracil in mouse mammary tumor model. BMC Cancer 2014 Jun 20;14:460. PMID: 24950740.
5. Zhulenkovs D., K. Jaudzems, A. Zajakina, A. Leonchiks. Enzymatic activity of circular sortase A under denaturing conditions: An advanced tool for protein ligation. Biochemical Engineering Journal, Volume 82, 15 January 2014, Pages 200–209. Science direct: S1369703X13003331.
6. Zajakina A, R. Bruvere, T. Kozlovska. A Semliki fores virus expression system as a model for investigating the nuclear import and export of hepatitis B virus nucleocapsid protein. Acta Virol. 2014, 58(2):173-9. PMID: 24957723.
7. Vasilevska J, Skrastina D, Spunde K, Garoff H, Kozlovska T, Zajakina A. Semliki Forest virus biodistribution in tumor-free and 4T1 mammary tumor-bearing mice: a comparison of transgene delivery by recombinant virus particles and naked RNA replicon. Cancer Gene Therapy J. 2012, Aug;19(8):579-87. PMID: 22722377.
8. Hutornojs V., Niedre-Otomere B., Kozlovska T., Zajakina A. Comparison of ultracentrifugation methods for concentration of recombinant alphaviruses: sucrose and iodixanol cushions. Environmental and Experimental Biology. 2012, 10: 117–123.
9. Niedre-Otomere B, Bogdanova A, Skrastina D, Zajakina A, Bruvere R, Ose V, Gerlich WH, Garoff H, Pumpens P, Glebe D, Kozlovska T. 2012. Recombinant Semliki Forest virus vectors encoding hepatitis B virus small surface and pre-S1 antigens induce broadly reactive neutralizing antibodies. Journal of Viral Hepatitis. Sep;19(9):664-73. PMID: 22863271.
10. Zajakina A, Niedre-Otomere B, Aleksejeva J, Kozlovska T. Alphaviruses: multiplicity of vectors and their promising application as vaccines and cancer therapy agents. "Medicinal Protein Engineering" Book Chapter, CRC Press, Taylor & Francis Group, Boca Raton London, New York, 2009, pp. 519-532.
11. Aleksejeva J, Sominska I, Brūvere R, Ose-Klinklāva V, Zajakina A, Kozlovska T. 2008. Expresion of hepatitis C virus structural genes controlled by alphaviral recombinant replicons. Acta Biol. 745: 115-130.
12. Braun S, Zajakina A, Aleksejeva J, Sharipo A, Brūvere R, Meisel H, Pumpēns P, Kozlovska T. 2007. Proteasomal degradation of HBV core protein from naturally occurring internally deleted core gene variants. J Medical Virology, 79(9):1312-21. PMID: 17607782.