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PDF file - 77K, GNE-317, but not vismodegib, reduces the levels of pAKT in the PPM model. Western blot analysis of lysates from allografts, treated as indicated.

PDF file - 286K,Proliferation is suppressed in PPM tumors. Phosphorylation of histone H3 (pH3) is tightly correlated with chromosome condensation during mitosis. PM tumors have a high frequency of pH3 positive cells, while in PPM and PPwt/loxpM tumors, pH3 positive cells tend to occur in restricted regions.

PDF file - 2507K, Tumors in PPwt/loxpM mice display MBEN histology, similar to PPM tumors, demonstrated by H&E staining. Scale bars represent 1 mm in the low magnification images, and 100 microm in the high magnification images.

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PDF file - 5347K, Illustration of CC3 IHC image analysis. Bright-field images of CC3 IHC were imported into ImageJ. Automated local thresholding (Niblack method) and watershed segmentation were used to identify all nuclei, and total nuclear area was calculated. Dark CC3 positive areas were subsequently identified using a predetermined intensity-based threshold, and the area representative of these regions was calculated, enabling us to calculate % CC3 positive area as a function of total nuclear area.

PDF file - 1233K, Loss of PTEN in Math1-expressing granule neuronal precursor cells results in ectopic positioning of enlarged NeuN-expressing cells.

Medulloblastoma is a cancer of the cerebellum, for which there is currently no approved targeted therapy. Recent transcriptomics approaches have demonstrated that medulloblastoma is composed of molecularly distinct subgroups, one of which is characterized by activation of the Hedgehog pathway, which in mouse models is sufficient to drive medulloblastoma development. There is thus considerable interest in targeting the Hedgehog pathway for therapeutic benefit in medulloblastoma, particularly given the recent approval of the Hedgehog pathway inhibitor vismodegib for metastatic and locally advanced basal cell carcinoma. Like other molecularly targeted therapies, however, there have been reports of acquired resistance to vismodegib, driven by secondary Hedgehog pathway mutations and potentially by activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Given that acquired resistance to vismodegib may occur as a result of inappropriate PI3K pathway activation, we asked if loss of the PI3K pathway regulator, phosphatase and tensin homologue (Pten), which has been reported to occur in patients within the Hedgehog subgroup, would constitute a mechanism of innate resistance to vismodegib in Hedgehog-driven medulloblastoma. We find that Hedgehog pathway inhibition successfully restrains growth of Pten-deficient medulloblastoma in this mouse model, but does not drive tumor regression, as it does in Pten-wild-type medulloblastoma. Combined inhibition of the Hedgehog and PI3K pathways may lead to superior antitumor activity in PTEN-deficient medulloblastoma in the clinic. Cancer Res; 73(23); 7034–42. ©2013 AACR.