In many tumors, chemotherapy, surgical resection, and other recently used Anti-cancer techniques has always been risky, with broad spectral effect and many side effects. Moreover, having a little if any effect on cancer progression.

Lately, a new technique has been developed called “viral oncolytic therapy” using genetically modified viruses to kill specific targeted cancer cells. for example, T-VEC, an approved FDA treatment for melanoma is made from a genetically modified herpes virus.

Could we do more?

In this article, the treatment of glioblastoma multiform; a highly progressive primary brain tumor, using Zika Virus will be discussed.

 

Glioblastoma:

Also known as, glioblastoma multiform and stage IV astrocytoma is the most aggressive primary brain tumor.

Signs and symptoms of glioblastoma are non-specific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke.

Not sure if tumors could be called magnificent; but this one here definitely is. The way it propagates is insane!

Classic tumors tend to grow in a circumferential form that can be detected, resected, and done with using certain doses of chemotherapy. Glioblastoma however, differs in that it shows a certain growth pattern “multiform” while in a cellular level; that cannot be detected by doctors, tiny stem cells are sent throughout the brain commissures, making multiple tumor foci and thus multiple sites of reoccurrences.

 

Zika Virus:

Is a mosquito-borne flavivirus that was first identified in Uganda in the year of 1947 in monkeys.

ZIKA V infects the developing CNS, with neural stem and progenitor cells prominently affected. The effects of ZIKA V in adults are generally less severe if any, and last for 2-7 days.

Thus, it was hypothesized that the preference of Zika virus for neural precursor cells could be used against glioblastoma stem cells “the reason for tumor reoccurrence”. 

 

Did it Work?

 

1) In vitro:

Patient-derived glioblastoma stem cells (GSCs) that expressed stem cell markers, self-renew, have a differentiation potential were taken, as well as differentiated glioma cells (DGCs).

both cells were then infected with representative African, and American ZIKA V strains.

Result:

  1. A) GSC proliferation was abolished by either ZIKA V strain, whereas DGCs were nearly unaffected.
  2. B) ZIKA V also reduced GSC sphere formation.

 

2) In human tissue specimens:

Glioblastoma specimens were collected and inoculated with the two ZIKA V strains.

Normal neural tissues were also inoculated from adult epilepsy specimens to test the effects of ZIKA V on normal adult human neural cells.

Result:

  1. A) ZIKA V did infect proliferating cells but still rarely infected DGCs.
  2. B) ZIKA V did not infect normal adult human brain tissues, as limited viral replication was detected compared with glioblastomas.

 

3) In Mice:

Mice with aggressive glioma were randomized into two groups and treated with either PBS control “a cellular isotonic saline” or mouse-adapted ZIKA V-Dakar and validated by histopathology. ZIKA V antigen and markers of stem cell proliferation and differentiation were also stained to determine the specificity of cell targeting.

Result:

A) Histological examination demonstrated that the ZIKA V-treated tumors were smaller in size compared with PBS-treated tumors. ZIKA V infection also extended the life spans of tumor-bearing mice.

-The majority of ZIKA V infected cells expressing the precursor marker SOX2.

-70% were negative for Ki-67.

B) 2 weeks after treatment, viral RNA remained localized to the tumor, and ZIKA V-treated tumors had extensive cell death as assessed by caspase-3 staining.

 

  • Last, Combinatorial efficacy of TMZ and ZIKA V-E218A “a modified strain of the virus”. Whereas TMZ alone had limited effects on GSCs, ZIKA V-E218A combined with TMZ for 1 week showed greater anti-tumor efficacy and induction of apoptosis.

 

In Conclusion:

Because of its tropism for neuroprogenitor cells, ZIKA V may offer a tailored therapy that could be used in combination with conventional therapies (TPZ) that target bulk tumor cell populations. Moreover, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.


 

References:

1-Bruce, MD, J. N. (2018, January 31). Glioblastoma Multiforme: Practice Essentials, Background, Pathophysiology. Retrieved from https://emedicine.medscape.com

2-Zika virus. World Health Organization 2018. http://www.who.int/news-room/fact-sheets/detail/zika-virus#.WwiPFL5le-c.link (accessed May 25, 2018).

3-Zhu Z, Gorman MJ, McKenzie LD, Chai JN, Hubert CG, Prager BC, et al. Zika virus has oncolytic activity against glioblastoma stem cells. JEM 2017. http://jem.rupress.org/content/early/2017/09/05/jem.20171093 (accessed May 25, 2018).

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