ly-2157299 and Medulloblastoma

Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFβ/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFβ/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autocrine Communication; Cell Line, Tumor; Cell Proliferation; Cerebellar Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibin-beta Subunits; Medulloblastoma; Membrane Proteins; Mice, Nude; Phosphorylation; Pyrazoles; Quinolines; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta3; Tumor Burden; Xenograft Model Antitumor Assays