Cancer has been among the leading causes of death throughout the world for decades, devastating many families with its commonly low survival rates and limited treatment options. In particular, Glioblastoma, arguably the most aggressive form of cancer, is fatal with the median survival rate being 10 to 12 months[1] (even when accompanied with treatment) due to how developed the grade IV tumour is. Because of this reason, it is also one of the most researched topics within oncology with promising treatment techniques being discovered every year. One of these potential treatments involves the use of an adapted form of the Zika virus, a pathogen which was responsible for disease epidemics primarily from 2015 to 2016, particularly in Brazil. Scientists have found a way to alter the virus and use it as a means to benefit the treatment of certain malignant tumours. One of the prime effects of the virus is that it hinders neural development in fetuses, causing the microcephaly seen in children. This characteristic of the virus presented itself as an ideal mechanism to study within cancer research, as the reducing effect of the virus could be directed into slowing cell division instead of neural development, giving it good potential for future testing.
The cycle of the Zika virus
The Zika virus (ZIKV) is categorised as a flavivirus and was first identified in the Zika forest in Uganda (1947)[2] when it was noticed in a rhesus sentinel monkey and was consequently isolated. The first record of a ZIKV infection in humans was in 1954, Nigeria[4], where a young 10 year old child was found to be carrying the virus in the midst of an epidemic of jaundice taking place in Africa.
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The Zika virus is found within the family of Flaviviridae and the genus Flavivirus and is classified as an Arbovirus. It is a single stranded RNA virus in an icosahedral structure, with similarities to other members of the Flavivirus genus such as the West Nile virus. An Arbovirus is an arthropod borne virus which is carried throughout nature by the means of biological transmission from susceptible vertebrate hosts to hematophagous (vector) arthropods including mosquitoes.
The virus’s main means of transmission is through the bite of an Aedes Aegypti mosquito, found across the world but its place of origin as well as its highest population, is in Africa. The females of the Aegypti species must bite animals or humans as they require certain proteins to activate the vitellogenin gene, starting the production of yolk protein which then causes egg production within the ovaries. They get these proteins as well as others which help to sustain the eggs, from the components of blood. So the cycle of ZIKV transmission begins when the mosquito first feeds on the blood of a person who is a carrier of the Zika virus. The ZIKV in their blood is then transferred to the mosquito, where it is ingested and then the virus proceeds to reproduce in the epithelial tissue of the midgut. As the ZIKV replicates, it spreads to glands, most importantly the salivary glands where it remains for an incubation duration of 10 days. After this time, the mosquito now becomes a vector to the ZIKV, gaining the ability to transfer it to another being through the exchange of fluids when feeding on blood. As the feeding takes place, the virus infects the other organism’s dermis layer and replication occurs. It can also go on to infect the fetus of those pregnant by passing through the placental barrier. This sylvatic cycle then continues.
Why ZIKV was an ideal virus to study within oncology
The virus infects many people, however most cases are merely mild infections and are not harmful, whereas the infection is more concerning for pregnant women. This concern originates from the evidence that ZIKV causes different defects in the fetus. For example, congenital microcephaly, cerebral atrophy, intracranial calcifications (calcium deposits) and hydranencephaly (missing front hemispheres). These symptoms stem from a reduced effect of neural development, caused by the mechanism of the ZIKV. These reducing and hindering characteristics of the virus, presented themselves as ideal aspects to study within the field of oncology, with the intention that with further research and investigation of ZIKV, the reducing effect could be channeled into limiting the uncontrollable cell division and mutation that defines cancer.
Overview of GBM treatment options
A particularly aggressive form of cancer is Glioblastoma Multiforme (GBM). Glioblastoma is defined by the National Cancer Institute as ‘a fast-growing type of central nervous system tumor that forms from glial (supportive) tissue of the brain and spinal cord’[3]. Although it can be found in the spinal cord, it is much more common in the brain which is why Glioma is used as a general term to identify primary brain tumors. Gliomas can be graded ranging from grade I to IV, with IV being highly malignant as well as invasive, compared to grade I where the cancer can often be eliminated with surgery. So far, no exact carcinogenic causes of the tumors have been identified and the only risk factor is exposure to high levels of ionising radiation, which may cause a genetic mutation, unlike other cancers where there are multiple risk factors such as smoking or obesity. The most common site of tumor formation is the supratentorial region of the cerebral hemisphere. Glioblastoma is particularly fatal due to the detrimental effect of the uncontrollable mitotic activity in the brain hemispheres. This formation of a mass can impair certain functions, depending on its location. For example, if the mass disrupts the frontal lobe tissue, psychiatric disturbances could occur, or if in the temporal lobe, hearing or vision could be affected. Seizures are also common as well as hemorrhages, which are likely to progress to a fatal level.
Evaluation of common treatment options
As of today there are no definitive curative treatment methods but there are treatments to prolong life for up to 3 years more, usually aimed at shrinking the tumor. Surgery to resect the tumor is often the most invasive but effective method of treatment. The surgery begins with the neurosurgeon performing a craniotomy to allow access through the skull and into the portion of brain tissue where the glioma is situated. There are multiple types of craniotomies such as stereotactic craniotomies where imaging such as MRI or CT scanners are used to allow the surgeon to distinguish between healthy brain tissue and cancerous tissue. Another method used for visualisation is fluorescence guided surgery where fluorescein is used to make the tumor glow. The surgeon will then resect as much of the tumor as possible since recurrence of the tumor is expected at anything over a 2cm margin of the resection, whilst being careful not to damage too much healthy tissue as this could have disastrous effects. These effects could be loss of speech, memory, sight, movement etc, all depending on where the primary site of the tumor is located. In order to avoid any complications like this, the surgery can be done whilst the patient is fully conscious. This is called intraoperative brain mapping. Awake surgery is common when the glioma is less defined and has unclear margins. The neurosurgeon needs constant feedback to see if any key brain functions have been affected, due to the destroyal of the brain tissue.
After an attempt at surgery or if the tumor was inoperable, the next stage of treatment is generally chemotherapy and radiation therapy. The chemotherapy most commonly used is temozolomide with it being used everyday during radiotherapy, then six maintenance cycles after. Temozolomide has a cytotoxic effect through methylation, which suppresses gene transcription and stops the activity of the DNA. Targeted drug therapy can also be used which eradicates specific cells, leaving surrounding brain tissue undamaged by the toxic effects often inflicted during other therapies such as radiation or chemotherapy.
Why Glioblastoma is difficult to treat
Despite all of these options, Glioblastoma is still extremely difficult to treat as a result of its place within our most vital cells and its predilection to recur. Due to its location in the brain and spinal cord, most treatment damages large sections of vital healthy tissue as well as cancerous cells. Depending on the number of damaged cells, the patients could lose partial function of certain regions of their brain, or nerves in the spinal cord could be affected. This can be avoided by attempting to restrict the range of radiation or chemo but that increases the risk of recurrence since not all of the tumor will have been destroyed which allows the cancer to continue to divide. However there are always multiple clinical trials or preclinical trials as well as in depth research taking place, with the purpose of finding many more effective treatment options of Glioblastoma.
Virotherapy evaluation
One of these preclinical trials is investigating the adaptation of the Zika virus and its treatment of Glioblastoma. This is Virotherapy, a type of targeted therapy and is the method of changing gene expression in viruses to convert them into therapeutic agents capable of oncolytic activity.
Virotherapy comes with many beneficial aspects. Arguably the most important advantage is that replication of the virus only takes place within malignant cells. This therefore prevents compromising any healthy tissue for the sake of stopping cell division. The selected viruses only lyse tumor cells due to the particular cell surface receptors on their membranes, meaning the DNA of healthy cells remain unchanged unlike in chemo and radiotherapy where the field of treatment is more generalised. Another advantage of virotherapy is its ability to mark tumor cells which have dissipated around the body via the bloodstream, instead of being limited to a single large collection of malignant cells in one location. So the cancer can be potentially eradicated all at once, instead of in degrees, drastically cutting down on treatment time.
On the other hand, virotherapy does have some disadvantages, the main one being the chance of the immune system clearing the virus before any oncolytic activity has the chance to take effect. This is due to the body recognising the virus as foreign and prompting an immune response. This means that the virus does not always get the chance to lyse the tumor cells and eliminate the cancer so the treatment doesn’t guarantee success, potentially wasting time which could have been spent doing more tried and tested treatments. However, many doctors understand this and don't use virotherapy as a stand alone method but rather incorporate it into other treatments such as chemotherapy and radiation. The multiple treatments can then work together to maximum effect ensuring the patient is getting the most effective treatment plan.
Preparation of the treatment
The Zika strain used was the Dakar 41519 and the Cambodian FSS13025 strain, developed from its complementary DNA chain. The Cambodian strain was chosen for mutagenesis as the clone was easier to access. The Dakar strain was passaged through a RAG-1-deficient (immunodeficient) mouse 4 times, to create a variant of ZIKV more inclined for infection due to a mutation in its NS4B gene. The Cambodian ZIKV was added to a diluted Temozolomide solution with the dissolution of phosphate buffered saline and ZIKV was added at a multiplicity of infection of 5.
Effectiveness of the ZIKV
The ZIKV was then inserted into the glioblastoma stem cells and an increase in apoptosis occurred. Apoptosis showed that the virus was successful in infecting the cells as there was more programmed cell death resulting in the shrinkage of the tissues, something that unaffected cancer cells are unable to do as the apoptotic pathway is dysfunctional. The B cell lymphoma-2 (Bcl2) expression was also regulated. This is a gene that can be responsible for either limiting apoptosis or inducing it, so is extremely important in the cell cycle. Overall, the virus was successful in treating the glioblastoma stem cells and inducing the microRNA 34c (MiR34c) expression which is a family of RNA that suppresses tumor growth.
Evaluation of the first stages of the ZIKV and GSCs trial
Overall, the study seems to have a solid foundation for continuation of a clinical trial as this is just its first stage out of many phases left to come. This study is not yet at a clinical trial level yet, instead it is in a period of preclinical testing. This means the treatment is not developed enough yet to test on humans, and remains in the lab. Generally, the preclinical studies are a result of extensive research channeled into a particular treatment whether it be vaccinations or antivirals and so on, or in this case, a virotherapy drug. The first stage of a preclinical trial is testing on artificially cultured tissue which was made to replicate whichever type of cell the treatment is focused on, in this case glioblastoma cells. The cells used in this trial were stem cells developed into GSCs. Possibly the most important aim of this stage is to test the drug’s efficacy. It allows scientists to observe the subcellular effects of the treatment and allows them to evaluate if it is effective against the targeted cells. If it is not then the drug is either altered further to improve the efficacy or sometimes discarded altogether if the treatment is deemed unsuccessful. Testing on animals usually follows this. This is done to observe any side effects the animals may have that could transfer to humans when they receive the treatment. Animal testing is always a heavily debated topic and presents both advantages and disadvantages although it is still widely used within testing for cancer treatments as it can benefit millions of patients.
This preclinical trial of the ZIKV and GSCs appears to have gone well. The efficacy of the virotherapy was confirmed in the studies and shown by the apoptosis of the cells, and there weren’t any complications to do with damage of the healthy stem cells. Most substances don’t advance past this stage of lab testing due to a lack in efficacy so this treatment does show promise compared with some other attempts at cancer treatment.
However, although the trial has not faced any major setbacks yet, the preclinical testing is not fully developed yet since no animal testing has taken place. This means that there could in fact be issues with the virotherapy when introduced to full working organisms but we are currently unaware of them since the treatment has not been tested that far yet. Therefore this lack of development in the preclinical trial is its main downfall as future problems may remain uncovered.
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