Novel therapeutic targets in pediatric neural tumors

The embryonal tumors neuroblastoma and medulloblastoma are two of the most common and deadliest tumors in childhood. Both are heterogeneous tumors that arise in the peripheral and central nervous system, respectively. The observed heterogeneity in these tumors is reflected by patient outcomes, where patients with favorable, low-risk tumors, have survival rates exciding over 90%. In contrast, patients classified as high-risk show an aggressive tumor behavior with survival rates of less than 40%. Because of aforementioned reason, there is a great need of finding novel and better therapeutic approaches for patients with high-risk disease.

Cancer is a disease where normal cells divide in an uncontrolled fashion, propagating and invading nearby and distant tissues, shrewdly circumventing cell intrinsic, and external defense mechanisms against oncogenic transformation. Cancer cells hijack and deregulate signaling networks that in normal cells regulate fundamental processes. In this thesis, several cellular networks are investigated, namely Hedgehog (HH), Wingless (Wnt), DNA repair and the DNA damage response (DDR) pathway, with the aim to identify novel therapeutic targets in neuroblastoma and medulloblastoma.

Neuroblastoma has been linked to aberrant HH signaling. Here we demonstrate that the GLI oncogene is highly vulnerable in non-MYCN amplified high-risk neuroblastomas tumors. The GLI antagonist GANT61 inhibited neuroblastoma growth in preclinical models, and potentiated the cytotoxic effects of conventional chemotherapeutic drugs. Our findings suggest that targeting the HH signaling in neuroblastoma is a highly attractive therapeutic target for high-risk neuroblastomas (Paper I). The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is associated with chemoresistance and is frequently overexpressed in cancer. In search for modulating MGMT activity to restore chemosensitivity in neuroblastoma and medulloblastoma, we found a novel link between Wnt signaling and MGMT gene regulation. By breaking this interaction through pharmacological and genetic inhibition we demonstrate that MGMT expression is suppressed and sensitivity to chemotherapy is restored. These results provide a basis of combining Wnt inhibitors with chemotherapy in patients with high MGMT expression (Paper II). One of the most common chromosomal abnormalities found in neuroblastoma and medulloblastoma and predictor of adverse outcome is gain of the q-arm of chromosome 17 and isochromosome 17q. The p53 protein phosphatase magnesium-dependent 1 delta (PPMID)/Wild-type p53 induced phosphatase 1 (WIP1) is suggested by several reports to be one of the putative oncogenes located on 17q. Our study demonstrates that PPM1D/WIP1 can be activated through several mechanisms, including copy number gain, gene amplification, alternative splicing and oncogenic mutations. Moreover, PPM1D/WIP1-transgenic mice develop a variety of cancers following external DNA stress, thus confirming the oncogenic role in cancer development. Our preclinical genetic, molecular, and pharmacological findings propose WIP1 as a novel therapeutic target in neuroblastoma and medulloblastoma (Paper III).

List of scientific papers

I. Wickström M, Dyberg C, Shimokawa T, Milosevic J, Baryawno N, Fuskevåg OM, Larsson R, Kogner P, Zaphiropoulos PG, Johnsen J. Targeting the hedgehog signal transduction pathway at the level of GLI inhibits neuroblastoma cell growth in vitro and in vivo. International Journal of Cancer. 2013;132(7):1516-24.
https://doi.org/10.1002/ijc.27820

II. Wickström M, Dyberg C, Milosevic J, Einvik C, Calero R, Sveinbjörnsson B, Sandén E, Darabi A, Siesjö P, Kool M, Kogner P, Baryawno N, Johnsen JI. Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signaling prevents chemoresistance. Nature Communications. 2015;6:8904.
https://doi.org/10.1038/ncomms9904

III. Milosevic J, Treis D, Gallo G, Fransson S, Wickström M, Gulyas M, Elfman L, Sveinbjörnsson B, Hertwig F, Bartenhagen C, Wilhelm M, Abel F, Javanmardi N, Thankaswamy-Kosalai S, Eissler N, Tanino K, Matthias Fischer, Kool M, Sakaguchi K, Kanduri C, Baryawno N, Martinsson T, Johnsen JI, Kogner P. The PPM1D encoded WIP1 phosphatase is significant for cancer development and tumor progression and provides a therapeutic target in neuroblastoma and medulloblastoma. [Manuscript]