Medulloblastoma (MB) is the most common malignant brain tumor in children. Its rapid growth and tendency to spread through the nervous system necessitate the use of extreme aggressive and toxic therapies. Even with such therapies, a significant proportion of patients die from this disease, and survivors often suffer severe long-term side effects such as cognitive deficits and endocrine disorders. Improved strategies for treating MB are urgently needed. The goal of this study is to explore the targeted therapeutic approaches for MB. Preliminary studies suggest that a cytoskeletal protein, Nestin is essential for MB cell proliferation. In this proposal, investigators will further determine the mechanisms for Nestin in promoting MB development. In addition, recent studies have revealed that leukotriene, a lipid mediator, is required for Nestin expression in tumor cells and inhibition of leukotriene synthesis significantly prevents tumor cell proliferation. This study therefore proposes to examine the therapeutic potentials of leukotriene inhibitors in treating MBs in mice. These studies would significantly deepen our understanding of the molecular basis for MB development, and pave the road for the application of leukotriene inhibitors in treating human MB.
Identifying the critical role of Nestin in medulloblastoma development will contribute to our understanding of the molecular basis for this disease. Moreover, demonstration of the requirement of leukotriene for Nestin expression and tumor progression will facilitate the potential therapeutic application of leukotriene inhibitors for treting human medulloblastoma.
|Gordon, Renata E; Zhang, Li; Peri, Suraj et al. (2018) Statins Synergize with Hedgehog Pathway Inhibitors for Treatment of Medulloblastoma. Clin Cancer Res 24:1375-1388|
|Gordon, Renata E; Zhang, Li; Yang, Zeng-Jie (2017) Restore the brake on tumor progression. Biochem Pharmacol 138:1-6|
|Liu, Yongqiang; Yuelling, Larra W; Wang, Yuan et al. (2017) Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion. Cancer Res 77:6692-6703|
|Li, Peng; Lee, Eric H; Du, Fang et al. (2016) Nestin Mediates Hedgehog Pathway Tumorigenesis. Cancer Res 76:5573-83|
|Yuelling, Larra W; Du, Fang; Li, Peng et al. (2014) Isolation of distinct cell populations from the developing cerebellum by microdissection. J Vis Exp :52034|
|Li, Peng; Du, Fang; Yuelling, Larra W et al. (2013) A population of Nestin-expressing progenitors in the cerebellum exhibits increased tumorigenicity. Nat Neurosci 16:1737-44|