PPM1D/WIP1 in medulloblastoma

Medulloblastoma is the most common malignant brain tumor in children. Current multimodal treatment regimens consisting of surgery, radiation, and chemotherapy, as well as advances in imaging, have contributed to increased survival rates over the past decade. Patients with newly diagnosed disease demonstrate survival rates that range from less than 50% to greater than 90%, depending on the molecular subgroup [1]. However, survivors can develop severe, long-term treatment-related neurologic, cognitive, and endocrine sequelae. In addition, approximately 30% of patients experience disease recurrence, for which there are currently no effective standard therapies. The median survival of patients with relapsed/refractory medulloblastoma is less than one year, indicating a major unmet clinical need. Development of effective therapies for relapsed/ refractory medulloblastomas requires an understanding of the mechanisms mediating disease progression and/or drug resistance. Gene expression profiling studies have demonstrated that medulloblastomas can be stratified into at least four molecularly-distinct subgroups according to activation of wingless (WNT) or sonic hedgehog (SHH) signaling, or as Group 3 or Group 4 tumors. Medulloblastomas with nodular, desmoplastic histology usually exhibit active SHH signaling and are generally associated with an excellent survival prognosis. One study reported that high expression of the G protein-coupled receptor, CXCR4, defines a distinct subgroup of SHH-driven medulloblastomas that are more common in younger patients and characterized by a desmoplastic histology [2]. However, in the presence of GLI2 amplification or TP53 mutation, SHH-activated medulloblastomas demonstrate a dismal survival prognosis of less than 50% [1]. Patients with Group 3 medulloblastoma have an increased incidence of poor prognostic features, including MYC amplification, gain of chromosome 17q, and leptomeningeal metastasis at diagnosis, along with the worst prognosis for survival among all medulloblastoma subgroups. Group 4 tumors constitute the largest medulloblastoma subgroup and also exhibit gain of chromosome 17q, with or without 17p loss, along with leptomeningeal metastasis. However, survival is intermediate between that of WNT and Group 3 medulloblastomas. PPM1D/WIP1 (protein phosphatase, magnesium-dependent 1, delta; wild-type TP53-induced phosphatase 1) on chromosome 17q22-23 encodes a serine/threonine protein phosphatase, which regulates DNA damage response, in part through inhibition of p53. Amplification, overexpression, or mutation in the C-terminal domain causes WIP1 to gain oncogenic functions. Approximately two-thirds of medulloblastomas demonstrate amplification or overexpression of WIP1 [3,4]. We previously demonstrated that patients with medulloblastomas that express high levels of WIP1 have an increased incidence of metastasis and inferior progression-free and overall survival [5]. Gene expression analysis indicated up-regulation of metastasis genes, including …