PTPS-05PID1 NEGATIVELY REGULATES GROWTH OF INTRACRANIAL MEDULLOBLASTOMAS IN VIVO IN BarTeL MICE

BACKGROUND: PID1 mRNA level in medulloblastoma and glioma brain tumors is highly correlated with molecular subgroups, with more aggressive tumors having lower PID1 mRNA. Tumor PID1 mRNA level is also highly correlated with survival in patients with medulloblastoma and glioma in univariate and multivariate analyses. We also showed that in cell culture PID1 has a growth inhibitory effect (Erdreich-Epstein et al, Clinical Cancer Research 2014). We now demonstrate the in vivo effects of PID1 increase and deficiency on medulloblastoma growth. METHODS and RESULTS: We utilized our genetically engineered luciferase-imageable BarTeL mouse model of medulloblastoma in which the avian virus receptor Tva and luciferase are regulated by a Barhl1 promoter. Cerebellar cells from BarTeL mice were harvested at age 5 days and transduced ex vivo with avian viral vectors carrying either Shh and Mycn, or Shh, Mycn and Pid1. Transduced cells were then injected into the posterior fossa of immune competent, transplant-compatible mice. The increase in luciferase bioluminescence was significantly slower in cerebella of mice injected with Shh/Mycn/Pid1-transduced cells compared to Shh/Mycn. Median time to euthanasia was only 13 days for mice with Shh/Mycn medulloblastomas compared to 29 days in mice injected with Shh/Mycn/Pid1-transduced cells (p = 0.0007, n = 10 mice per group), indicating inhibition of medulloblastoma growth in vivo by Pid1. We then induced medulloblastomas in Pid1-deficient BarTeL mouse pups compared to non-deficient BarTeL pups by direct cerebellar injection of an RCAS avian virus carrying Shh and Mycn. In this case, medulloblastomas necessitated euthanasia in the Pid1-deficient BarTeL mice significantly faster than in the non-deficient BarTeL mice (median survival 47 days vs. 59 days, respectively, n = 30-32, p = 0.0023, Logrank for trend), indicating that Pid1 deficiency accelerated medulloblastoma growth. CONCLUSION: In addition to its in vitro growth inhibitory effects in medulloblastoma, PID1 inhibits medulloblastoma growth in vivo and its deficiency accelerates it.