The most common cytogenetic lesions in the embryonal neural tumors medulloblastoma (MB) and neuroblastoma (NB) affect chromosome 17, with 17q+ or isochromosome 17q, in approximately one-third of MB with these aberrations being a significant indicator of poor clinical outcome. Similarly, in NB gain of 17q is the most powerful genetic predictor of adverse clinical outcome. 17q+ correlates with poor survival in our population-based material where we found aberrations of chromosome 17 in 85% of primary neuroblastomas, specifically, gain of PPM1D/Wip1 at 17q23. Wip1 is a serine/threonine phosphatase encoded by the gene PPM1D, described as a gatekeeper in the Mdm2-p53 regulatory loop involved in genetic stability, inflammation and a potential oncogene contributing to carcinogenesis.
Comparative genomic hybridization (CGH) was used to examine PPM1D/Wip1 in neuroblastoma and medulloblastoma tumors and cell lines. Stable Wip1 knockdown SK-N-BE(2) cells were generated by shRNA transfections and tested in vivo in tumor xenografts. Pharmacological inhibition with the p53-mdm2 modulating inhibitors RITA, Nutlin-3 and a new PPM1D/Wip1 inhibitor, was used to evaluate the function of PPM1D/Wip1 in preclinical neuroblastoma and medulloblastoma models.
CGH-array analysis detected PPM1D/Wip1 extra copies in all tumors and cell lines containing 17q-gain. Tumor neuroblastoma xenograft development was significantly delayed showing median tumor development (0.10 mL) to be more than doubled (median 15 days, vs. 33 days, p<0.001) after Wip1 downregulation compared to scrambled controls. A novel Wip1 inhibitor was highly potent in cytotoxic/cytostatic effect in a variety of neuroblastoma and medulloblastoma cell lines. Furthermore, this Wip1 inhibitor significantly inhibited growth of established human neuroblastoma- and medulloblastoma tumors in nude mice after treatment (P<0.01).
Our results show that PPM1D/Wip1 is oncogenic in neuroblastoma and medulloblastoma development and provides a novel therapeutic target in these two childhood cancers of the nervous system. More studies investigating the effects of PPM1D/Wip1 inhibition are needed to evaluate its clinical significance.
Citation Format: Jelena Milosevic, Diana Treis, Malin Wickstrom, Susanne Fransson, Nina Eissler, Baldur Sveinbjörnsson, Ninib Baryawno, Keiji Tanino, Galina Selivanova, Kazuyasu Sakaguchi, Tommy Martinsson, John Inge Johnsen, Per Kogner. The PPM1D encoded phosphatase Wip1 is a novel oncogene and potential therapeutic target in neuroblastoma and medulloblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 503. doi:10.1158/1538-7445.AM2015-503