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Fall 2011

Poliovirus: A Promising Candidate for Effective Oncolytic Treatment of Neuroblastoma Amy Patel, ‘12

Have we finally developed a method to fight cancerous tumors, our callous rivals? Not exactly, but we have found an alternative to the adverse effects of chemotherapy and radiation therapy: oncolytic viruses. As infectious agents, viruses have been clinically proven to infect and lyse cancer cells, and have thus become a promising new class of antitumor therapy. Following viral replication, the engineered vectors act to destruct tumor cells and stimulate antitumor immune responses. While research has demonstrated successful results in animal models, efficacy on human subjects has been more restricted. Poliovirus is a recent addition to the list of oncolytic viruses that have therapeutic values. Interestingly, poliovirus has been proven to replicate efficiently in almost all tested tumor cell lines, making it an attractive approach for developing new treatment strategies against multiple cancers. [1] Poliovirus causes poliomyelitis, or polio, an illness that was first recognized in England in 1789, and reported in the U.S. in 1843. As the illness swept through developed nations in the Northern Hemisphere, the average age of the affected also increased, and consequently its severity. In 1952, paralytic cases radically elevated to about 21,000 in the U.S. A decline in polio cases occurred only after the certification of the poliovirus vaccine in the 1950s. Currently, this disease is almost extinct and only smatterings of cases are reported yearly throughout the world [2]. Poliovirus enters its host through ingestion and multiplies as it moves through the digestive tract. Unable to dissolve in the acidic conditions, it may stay intact and cause infection [2]. This non-enveloped, positive-stranded RNA enterovirus, a member of the family of Picornaviridae, may target motor neurons of the Central Nervous System (CNS), lead to poliomyelitis, and eventually death [3]. A virus can cause cell carcinogenesis by promoting harmful genetic alterations within the cellular DNA [4]. Because

viruses are an established cause of cancer, the introduction of these daunting infectious agents to an organism to impede tumor growth may seem unrealistic and doubtful. One may ask whether dangers such as paralysis by poliovirus invasion have been taken into account, or if vaccinations against polio given during childhood interfere with the ability of poliovirus to kill tumor cells in vaccinated children. Scientists were able to effectively account for these potential complications by designing experiments that tested each factor and resolved each issue [4]. This resulted in the development of highly attenuated polioviruses that would be suitable for tumor therapy without being noxious to healthy tissue. Additionally, an immunocompetent animal model resembling a human who has been vaccinated against polio was developed, which would allow for the examination of the oncolytic proficiency of neuroattenuated viruses [3]—viable viruses that have a marked reduction in their virulence towards the host [4].

Defining neuroblastoma and approaches towards its treatment Neuroblastoma is a form of cancer in which malignant cells form in the nervous tissue of the embryo or fetus. It occurs most often in infants and young children and has become a challenge for pediatric oncologists. [3,4] Resistance to conventional therapies, such as radiation therapy and chemotherapy, motivated researchers to find a new therapeutic approach to treat this tumor. Scientists proposed the introduction of a novel attenuated poliovirus as a promising oncolytic treatment of human neuroblastoma, even in the presence of polio immunity. Replication of the virus in neuroblastoma cells of mice, Neuro2aCD155, which expressed the gene for the primate poliovirus receptor CD155, resulted in the elimination of neural tumors without causing paralysis or death. Furthermore, re-inoculation of Neuro-2aCD155 did not show signs of tumor growth in mice cured of neuroblastoma, indicating that the destruction of tumor cells by poliovirus may induce a potential antitumor immune response. [3]

Successfully attenuating poliovirus[4]


After several trials, scientists in the laboratory of Dr. Cello at Stony Brook University found that a stable attenuation of poliovirus could be produced by the interception of the cisacting replication element (cre) into the “spacer region”. This spacer region is located between two domains, the cloverleaf and internal ribosomal entry site (IRES), in the 5’-nontranslated region (NTR), as shown in Figure 1. The native cre, a stem-loop structure, was duplicated and inactivated by 3 point mutations. Both mono-crePV and dual-crePV can replicate in human neuroblastoma, SK-N-MC, cells. However, it is less The Stony Brook Young Investigators Review, Fall 2011

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Fall 2011  

Fall 2011