WIP1 Modulates Responsiveness of MB to Genotoxic Stress.
Medulloblastoma is the most common malignant brain tumor in children. Approximately 1/3 of medulloblastomas gain the long arm of chromosome 17. Since the WIP1 cancer-causing gene is located on the long arm of chromosome 17, we investigated its expression in medulloblastoma tumor tissues and in cell lines derived from medulloblastomas.
We found that WIP1 was expressed at high levels in human medulloblastoma tissues and cell lines, especially in those with gain of the long arm of chromosome 17q. We further found that high expression of WIP1 prevented the cancer-inhibiting protein, p53, from responding appropriately to treatments such as radiation and chemotherapy, which are routinely used to treat children with medulloblastoma. This suggests that high WIP1 expression promotes medulloblastoma growth and also prohibits these tumors from responding to conventional treatments for medulloblastoma.
Our follow-up studies, published in Neuro-Oncology in 2012, show that high expression of WIP1 promotes medulloblastoma growth in tumors with normal, but not mutant, non-functional p53. Our studies suggest that WIP1 is a viable target for treatment of medulloblastoma. In the future we will use drugs that inhibit the function of WIP1 as well as its downstream signaling targets to treat mouse models of medulloblastoma and human medulloblastoma cells. Our long-term goal is to identify novel drugs that could be used with current or reduced doses of current treatments in order to improve both the cure rate and side effects of medulloblastoma treatment.
How has funding from ALSF made a difference in what you have been able to do?
ALSF funding gave me an opportunity to study a hypothesis that I might not have otherwise pursued. When I began the project funded by ALS, few scientists were interested in the role of p53 signaling in medulloblastoma tumor formation. Based on recent, relatively large genomic studies of medulloblastoma, this area of investigation is expanding. ALSF funding also gave me time and a track-record of funding which enabled me to obtain federal sponsored grant and allowed me to establish my own translational research laboratory at Emory University. I think that, as NIH funding continues to become more competitive, funding agencies such as ALSF will grow in their importance for the health both of research and the children whom it serve5.
Robert Castellino received a 2012 Springboard Grant , which then allowed him to secure his 1st R01 award from the NIH/NCI in 2013.