Research And Grants

Treatment of Diffuse Intrinsic Pontine Glioma with the Oncolytic Zika Virus.

Diffuse intrinsic pontine glioma (DIPG) is a devastating brainstem tumor affecting 150-300 children in the US per year. The overall rate of survival is dismal, with only 10% of children surviving beyond the second year from the time of diagnosis.[1]  Though a rare tumor with high mortality, DIPG represents 80% of pediatric brainstem tumors.[2]  One of the challenges in treating DIPG is its location in the pons and the relative protection of the blood brain barrier.  Despite advances, treatment for this aggressive tumor remains ineffective highlighting the absolute need for a novel therapy.  Our laboratory has identified Zika virus as an innovative oncolytic virus that is cytotoxic to DIPG cells in culture as well as in DIPG tumors grown in mice.  In order to explore this viable alternative therapy for DIPG, we examined related tumors and their treatment advances.  One of these related tumors is neuroblastoma, which is also a childhood cancer that occurs along nervous tissue and the adrenal glands.  Our published data established that neuroblastoma cells are killed by Zika virus. Furthermore, we validated a survival advantage for mice growing neuroblastoma tumors after treatment with Zika virus: all mice with neuroblastoma tumors revealed a complete loss of tumor mass after Zika viral injection therapy.  Our findings in neuroblastoma apply as a therapy for DIPG because of the similarity of their cellular origin.  Recently, a new method delivered a modified adenovirus directly into the pons of children with DIPG followed by radiation, resulting in a 33% survival rate at 20 months.[3] Although this confirms that direct viral delivery can be a feasible approach for treating DIPG, the adenoviral vector did not improve overall survival. This is where Zika virus can emerge as an effective therapy.  We envision using a similar direct delivery protocol, but using Zika virus, which is far more cytotoxic to DIPG, yet remains considerably safer than adenovirus to the patient and require no use of radiation.  

Because of a common cell lineage between neuroblasts and glial cells, we tested and confirmed that a single application of Zika virus killed >90% of both cell lines and patient derived DIPG cells in culture. In our preliminary mouse study, we successfully treated DIPG tumors grown on the mouse hindleg leading to greater than >90% loss of tumor mass with no side effects to the mice. As a result, we are pursuing the DIPG Collaborative Award to characterize the Zika viral killing of DIPG tumors grown directly in a mouse brain and investigate the requirement of the antiviral Type I interferon pathway in Zika viral cell death with our eventual goal aiming towards a phase 1 clinical trial.