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PPM1D Is a Therapeutic Target in Childhood Neural Tumors
Jelena Milosevic1,2, Diana Treis1, Susanne Fransson3
1Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, 17177 Stockholm, Sweden.
Abstract:
Childhood medulloblastoma and high-risk neuroblastoma frequently present with segmental gain of chromosome 17q corresponding to aggressive tumors and poor patient prognosis. Located within the 17q-gained chromosomal segments is PPM1D at chromosome 17q23.2. PPM1D encodes a serine/threonine phosphatase, WIP1, that is a negative regulator of p53 activity as well as key proteins involved in cell cycle control, DNA repair and apoptosis. Here, we show that the level of PPM1D expression correlates with chromosome 17q gain in medulloblastoma and neuroblastoma cells, and both medulloblastoma and neuroblastoma cells are highly dependent on PPM1D expression for survival. Comparison of different inhibitors of WIP1 showed that SL-176 was the most potent compound inhibiting medulloblastoma and neuroblastoma growth and had similar or more potent effects on cell survival than the MDM2 inhibitor Nutlin-3 or the p53 activator RITA. SL-176 monotherapy significantly suppressed the growth of established medulloblastoma and neuroblastoma xenografts in nude mice. These results suggest that the development of clinically applicable compounds inhibiting the activity of WIP1 is of importance since PPM1D activating mutations, genetic gain or amplifications and/or overexpression of WIP1 are frequently detected in several different cancers.
Insights
Childhood brain tumors like medulloblastoma and neuroblastoma rely on PPM1D for survival. The WIP1 inhibitor SL-176 effectively suppressed tumor growth in preclinical models, offering a potential new therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Childhood medulloblastoma and high-risk neuroblastoma often exhibit 17q gain, correlating with aggressive disease and poor prognosis.
- The PPM1D gene, encoding WIP1 phosphatase, is located within the 17q gain region and negatively regulates p53 activity, cell cycle control, DNA repair, and apoptosis.
Purpose of the Study:
- To investigate the role of PPM1D/WIP1 in medulloblastoma and neuroblastoma.
- To evaluate the therapeutic potential of WIP1 inhibitors, specifically SL-176, against these pediatric cancers.
Main Methods:
- Correlation analysis of PPM1D expression with chromosome 17q gain in cancer cells.
- Assessment of cancer cell dependency on PPM1D for survival.
- In vitro and in vivo efficacy studies of the WIP1 inhibitor SL-176 compared to Nutlin-3 and RITA.
Main Results:
- PPM1D expression levels correlated with 17q gain in medulloblastoma and neuroblastoma cells.
- These cancer cells demonstrated a high dependence on PPM1D for survival.
- SL-176 showed potent inhibition of medulloblastoma and neuroblastoma growth and survival, outperforming or matching other inhibitors.
- SL-176 monotherapy significantly inhibited established xenograft tumor growth in mice.
Conclusions:
- PPM1D/WIP1 is a critical survival factor for medulloblastoma and neuroblastoma.
- WIP1 inhibitors, such as SL-176, represent a promising therapeutic strategy for these pediatric cancers.
- Targeting WIP1 is relevant given its frequent alterations in various cancers.
