Research published in the Journal of Experimental Medicine gives new hope for treatment of a lethal type of brain cancer called glioblastoma. The collaborative work by researchers at Washington University, University of California and University of Texas used Zika Virus (ZIKV), which is endemic in the Americas, to target glioblastoma stem cells (GSCs).
What is Glioblastoma?
Glioblastoma is an aggressive form of brain cancer which affects cells called astrocytes, that have the important role of supporting nerve cells. Chemotherapy, radiotherapy and surgery are all routinely used to fight glioblastoma but are often unsuccessful; resulting in a median survival of only two years following diagnosis. These facts present a bleak picture for glioblastoma patients.
Glioblastoma stem cells (GSCs) or tumor initiating cells are one of the cell types responsible for the devastating features of this disease, as they promote tumor growth and are resistant to many anti-tumor therapeutic agents. They are thought to be the primary cause of cancer reoccurrence and treatment failure.
Killing GSCs, while avoiding non-diseased tissue, is one of the main challenges for the oncology field, and a concerted effort is being made to utilize natures natural cell invaders – viruses, to fight cancer.
ZIKV may be the answer
ZIKV is a member of the flavivirus family, which includes Dengue, Western Nile Virus and Yellow Fever Virus. ZIKV is spread by the Aedes aegypti mosquito and is most famous for its recent outbreak in the Americas and Caribbean where it has caused thousands of cases of ZIKV-induced fetal microcephaly, a congenital defect associated with a small head size and significant intellectual impairment. The virus causes these devastating effects by infecting cells similar to GSCs in adults and developing fetuses, preventing cell replication and causing cell death. While this viral trait has led to many tragic outcomes for parents and their infants, the authors of this work, Zhu et al, hypothesized that ZIKV may present the perfect weapon to target and kill GSCs in glioblastoma patients.
The researchers first took GSCs from patients and infected them with an African and American strain of ZIKV. 60% of cells were infected after 48 hours, and ZIKV prevented these cells from dividing normally and induced cell death. Interestingly, both strains of ZIKV infected significantly more cancer stem cells compared to normal tumor cells called differentiated glioma cells (DGCs). This appeared to be a trait unique to ZIKV, as exposure to the similar Western Nile Virus caused death in both cell types.
These observations were backed up by work with tumor tissue which had been removed from patients during surgery. ZIKV infected and killed GSCs without majorly affecting the DGCs and when the investigators exposed ZIKV to normal healthy brain tissue, they found that the virus did not enter cells and replicate, supporting the belief that ZIKV targets the GSCs and may have low toxicity in healthy tissue.
Cells in a petri dish are obviously not as complex as mammals like humans or mice. In order to test whether ZIKV could be used to target tumor stem cells in animals, Zhu and colleagues exposed mice that had been inoculated with glioma tumors, to mouse-adapted ZIKV.
After 1 week of ZIKV treatment, the tumors in the tumor-bearing mice had shrunk and remarkably, the ZIKV extended the life of these mice compared to the mice which did not receive viral treatment. Once again, the virus infected mainly tumor stem cells and did not spread to healthy tissue near the tumor site.
So how is ZIKV targeting the GSCs and not the normal tumor tissue?
The immune system has many ways in which it can remove invading viruses and one of these mechanisms involves the molecule interferon 1 (IFN-1). The researchers identified that IFN-1 is activated more in DCGs than in GSCs upon ZIKV infection, meaning, IFN-1 could stop ZIKV from infecting the DCGs and killing them. Indeed, when they blocked IFN-1 activity, they found that ZIKV infected and killed more DCGs!
Safety is one of the primary concerns when developing viral therapies, as there is always a risk the virus will infect cells and tissue which are not the primary target. Many successful viral therapeutic agents have been modified to disable their more undesirable characteristics, such as replication in infected cells. In order to enhance the safety profile of ZIKV, the investigators altered some of the viral genetic code. Both the natural ZIKV and the mutated version preferentially infected and killed GSCs over DCGs, however the mutated virus had the reduced ability to replicate in the infected cells, thus potentially making it less likely to infect surrounding healthy neural cells.
So how would treatment with ZIKV fit in with traditional cancer therapies? Like most cancers, chemotherapy is one of the main lines of defense against glioblastoma however, unfortunately chemotherapy resistance is a common problem and resistance in GSCs is often observed. Infection of GSCs with the mutated ZIKV together with the standard-of-care chemotherapy agent Temozolomide (TMZ), resulted in enhanced cell death compared to just TMZ alone.
There is obviously still much more to learn about how ZIKV functions and interacts with the mammalian cell; for example, the target which ZIKV binds to on the cell is still unknown. This work does however present the tantalizing prospect that ZIKV could be used in combination with conventional therapies to offer more effective treatment for aggressive and lethal glioblastoma cancers. Further work using genetic engineering to enhance the safety and effectiveness of ZIKV, could lead to the next step in neuro-oncology healthcare.
Zhe Zhu, et al, Zika virus has oncolytic activity against glioblastoma stem cells. (2017). Journal of Experimental Medicine, 214, (10). http://jem.rupress.org/content/early/2017/09/05/jem.20171093