Gene therapy inhibits tumor growth in medulloblastoma mice

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Utilizing the tumor suppressor function of Tis21, scientists provide early evidence for the use of gene therapy for inhibiting tumor proliferation in Medulloblastoma, the most common childhood brain tumor.

Comprising 15-20% of all pediatric brain tumors, medulloblastoma (MB) is the most common brain tumor in childhood and a major cause of pediatric mortality. Four major molecular subgroups of MB have been identified thus far: Wnt, Sonic hedgehog (Shh), subgroup 3 and subgroup 4.

Shh-dependent MBs arise from constitutive activation of the Shh signaling pathway, and lead to uncontrolled proliferation of cerebellar granule precursor cells (GCPs) in cerebellum resulting in the formation of neoplastic GCPs. Although several efforts have been put into developing Shh inhibitors for MB therapy, resistance to these small molecules has hindered further development of meaningful therapy for Shh-dependent MBs.

Tis21 gene which encodes a tumor suppressor protein has been shown to be linked to various cancers. It is also known to play an important role in cerebellar development and in the pathogenesis of MB. Previous studies showed that Tis21 was inversely correlated with the frequency of MB.

In the present study published in PloS One, researchers at Italy’s Institute of Cell Biology and Neurobiology of National Research Council evaluated the therapeutic potential of Tis21 in inhibiting tumor growth in MB allograft mice models. To do this, MB cells derived from mice heterozygous for Patched1 (a commonly used mice model for MB), a Shh receptor inhibiting the Shh pathway, were grafted subcutaneously in nude mice. Adeno-associated viral vector (AAV) encoding Tis21 gene (AAV-Tis21) were injected to the developing tumor nodules. Results showed that the treatment with the AAV-Tis21 slowed the growth of tumor nodules by reducing cell proliferation and promoting neural differentiation.

These findings suggest Tis21 as a potentially relevant target for gene therapy of MB and other brain tumors.

Source: Presutti D et al., Tis21-gene therapy inhibits medulloblastoma growth in a murine allograft model. PloS One March 2018.
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