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.
Highlights
Glioblastoma (GBM) is the most devastating and least treatable brain tumor, with an incidence of3.2 cases per 100,000 inhabitants [1]
In order to study the prevalence of CDKN2A in brain tumors, we performed an in silico analysis of 1018 glioma tumors
Our results revealed that GBMs have the highest occurrence of CDKN2A gene deletion among gliomas (Figure 1a). 76% of the GBM tumors included in this analysis (n = 428) were
Summary
Glioblastoma (GBM) is the most devastating and least treatable brain tumor, with an incidence of3.2 cases per 100,000 inhabitants [1]. Glioblastoma (GBM) is the most devastating and least treatable brain tumor, with an incidence of. GBM cells grow quickly and infiltrate the brain parenchyma [2]. Despite advances in medical image and novel therapies, the median overall survival is 15 months [4], suggesting that other alternatives are needed to find more effective treatment strategies for this heterogenous disease. In this sense, several molecular and genetic alterations have been observed that contribute to tumorigenesis and treatment resistance [5,6]. Some of the most relevant mutations in gliomas are the homozygous and hemizygous deletion at Ch9p21 [7], which involves the genetic loss of CDKN2A (p16INK4 ) [8,9]
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