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In test with mice, Zika virus eliminates human brain tumor common in children

April 26, 2018

A study published in the journal Cancer Research, of the American Association for Cancer Research, reveals the therapeutic side of the Zika virus, which in 2015 made global public health authorities wary when the link between the infection of the virus during gestation and the birth of children with microcephaly was established.

Now, Brazilian researchers at the Center for Human Genome and Stem Cell Studies at the University of São Paulo have put the virus to good use showing, for the first time in animals, the deleterious effect of the injection of a low concentration of the purified virus on human embryonic brain tumors induced in mice with low immunity. The article is called "Zika virus selectively kills aggressive human embryonal CNS tumor cells in vitro and in vivo" and was published online this Thursday. (link not available yet)

The studies were conducted using human cell lineages derived from two types of embryonic tumors of the central nervous system (CNS): medulloblastoma and atypical teratoid rhabdoid tumor (AT/RT). These are tumors that mainly affect children under 5.

"CNS tumors are the most common solid tumors in children and adolescents," explains Keith Okamoto, one of the study's lead authors. "The peak incidence of medulloblastoma is in children aged 4 to 5 years. AT/RT has a higher incidence in even younger children, of up to 2 years old."

In 20 of 29 animals treated with the Zika virus in the study, the tumors regressed. In seven of them (five with AT/RT and two with medulloblastoma), the remission was complete: the tumor disappeared. In some cases, the virus was also effective against metastases - it either eliminated the secondary tumor or inhibited its development.

Effect of the Zika virus on tumors in the brain and spine. The tumor cells are modified to emit light, which can be picked up with a specific equipment, producing a colored signal in the place where the tumors are. The images show the evolution of the tumors after the injection of the virus (Ti).

Mayana Zatz, coordinator of the center and one of the lead authors of the study, does not hesitate to describe the results as "spectacular". "We're going to have to handle the anxiety and not put the cart before the horse. It's very important to start with two or three patients, and if it works, do it for a larger number."

The next step will be to find partners for what is called, in the jargon of biomedical sciences, phase 1 tests, no longer in animals, but in people. In this case, mainly small children.

In order to do this, it will be necessary to obtain the purified virus in larger amounts and produced according to the good cultivation practices required for testing in humans. This stage is being treated with the Butantan Institute, which already provided the viruses and collaborated with the present study. From there, it will be possible to create a protocol for application in patients.

Carolini Kaid, a PhD candidate at the Center for Human Genome Studies supervised by Keith Okamoto, is the first author of the paper. She was especially responsible for dealing with the mice: she performed the surgeries to implant the tumors, injected the Zika virus on the spot, and then followed the evolution.

Ten in safety

Making sure the virus is safe is crucial to getting the study findings into the clinic. In this regard, the results of the article are promising. Concentrations of one viral particle per ten cells were sufficient to infect and kill cells derived from AT/RT and medulloblastoma tumors. In addition, the virus showed high specificity for this type of cells.

"The virus did not infect tumor cells indiscriminately," explains Okamoto. "It is quite specific for tumor cells of the nervous system." In addition, it also did not infect already differentiated neurons, which is a very advantageous behavior if repeated in humans with brain tumor.

The researchers also tested in vitro the functionality of viruses formed in tumor cells after infection. The results show that these new viral particles are defective, which would prevent uncontrolled virus spreading into the patient's body after antitumor treatment.

During the 2015 outbreak, hundreds of thousands of people were infected. Despite this, the majority of patients, children and adults, remained asymptomatic. Only a small proportion of infected people developed serious conditions, such as Guillain-Barré syndrome or encephalitis. These observations are very important when assessing the risks and safety of a new treatment.

"There is a very positive outlook," says Okamoto. "But there is a path still to be pursued so that we can move safely into the clinical part."

The experiments

The results of the study show that the Zika virus is capable of infecting and killing the cells of the CNS embryonic tumors with great efficacy and specificity both in in vitro and in mouse models.

The virus was tested in cells derived from prostate, breast, and colon tumors, in addition to three lineages of CNS embryonic tumors, a commercial one of medulloblastoma ("DAOY"), and two generated by the researchers themselves, one of medulloblastoma ("USP-13"), and another of AT/RT ("USP-7"). Concentrations of two viral particles per cell killed most of the CNS tumor cells, but had little effect on the other lineages. And even lower amounts of virus, of one viral particle per ten cells, inhibited the growth of CNS tumor cells.

The specificity of the virus was also evaluated in three-dimensional cultures, in which the effect was even clearer, showing that Zika's preference for stem cells from CNS embryonic tumors is even greater than that of neural progenitor cells.

In the in vivo experiments, embryonic CNS tumors, which are of human origin, were grafted onto mice. When these animals were treated with the Zika virus, most of the tumors showed remission and the metastases decreased.

The researchers were also able to relate the effects of the Zika virus to the molecular pathway of Wnt, a pathway that had previously been described as important in the development of AT/RT and medulloblastoma.
-end-


University of Sao Paulo Scientific Outreach Unit

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