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Newcastle Disease Virus (NDV) Oncolytic Activity in Human Glioma Tumors Is Dependent on CDKN2A-Type I IFN Gene
Noemi García-Romero1,2, Irina Palacín-Aliana3,4, Susana Esteban-Rubio5
1Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain.
Abstract:
Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor in adults with a median overall survival of 15 months. Tumor recurrence and poor prognosis are related to cancer stem cells (CSCs), which drive resistance to therapies. A common characteristic in GBM is CDKN2A gene loss, located close to the cluster of type I IFN genes at Ch9p21. Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic and immunostimulatory properties that has been proposed for the treatment of GBM. We have analyzed the CDKN2A-IFN I gene cluster in 1018 glioma tumors and evaluated the NDV oncolytic effect in six GBM CSCs ex vivo and in a mouse model. Our results indicate that more than 50% of GBM patients have some IFN deletion. Moreover, GBM susceptibility to NDV is dependent on the loss of the type I IFN. Infection of GBM with an NDV-expressing influenza virus NS1 protein can overcome the resistance to oncolysis by NDV of type I-competent cells. These results highlight the potential of using NDV vectors in antitumor therapies.
Insights
Glioblastoma (GBM) treatment resistance is linked to gene loss. Newcastle disease virus (NDV) shows potential for treating GBM, especially when type I interferon gene deletions are present.
Area of Science:
- Oncology
- Virology
- Genetics
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis, often linked to cancer stem cells (CSCs) and therapy resistance.
- Loss of the CDKN2A gene, near type I interferon (IFN) genes on chromosome 9p21, is common in GBM.
- Newcastle disease virus (NDV), an avian paramyxovirus, possesses oncolytic and immunostimulatory properties, making it a candidate for GBM treatment.
Purpose of the Study:
- To investigate the role of the CDKN2A-IFN I gene cluster in GBM.
- To evaluate the efficacy of NDV as an oncolytic agent against GBM, particularly in relation to type I IFN gene status.
- To explore strategies for overcoming NDV resistance in GBM.
Main Methods:
- Analysis of the CDKN2A-IFN I gene cluster in 1018 glioma tumor samples.
- Assessment of NDV oncolytic effects on six GBM CSCs ex vivo.
- Evaluation of NDV efficacy in a mouse model of GBM.
- Testing of NDV engineered to express influenza virus NS1 protein.
Main Results:
- Over 50% of GBM patients exhibit deletions within the type I IFN gene cluster.
- GBM susceptibility to NDV oncolysis is significantly influenced by the presence or absence of type I IFN genes.
- Engineered NDV expressing influenza virus NS1 protein can overcome resistance in type I IFN-competent GBM cells.
Conclusions:
- Type I IFN gene status is a critical factor determining GBM response to NDV therapy.
- NDV holds promise as an oncolytic agent for GBM, especially in tumors with specific genetic alterations.
- Genetically modified NDV vectors offer a potential strategy to enhance antitumor efficacy in GBM.
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