Medulloblastoma is the most common malignant brain tumor in children. Despite the progress in current cancer therapy, more than 30% of patients with medulloblastoma still die within 5 years after diagnosis. Moreover, the survivors often suffer severe side effects of tumor treatment, including endocrine disorders, coordination problems and increased tumor incidence in other parts of the body. Therefore, new strategies for the treatment of medulloblastoma are highly desirable.
Recent therapeutic strategy based on inhibition of Sonic hedgehog (Shh) signaling, a pathway that is aberrant activated in many cases of cancer including medulloblastoma, has significant limitations. Due to the fact that the Shh signaling pathway plays an important role in the normal development and proliferation of neural progenitor cells, its transient inhibition can cause severe adverse on-target effects. Although some Shh inhibitors have been developed as potential anticancer agents and are promising for some types of tumors, new therapeutic strategies and inhibitors that selectively target tumor cells over healthy cells are needed.
Summary of the Invention
Working with the experimental model of medulloblastoma in mice, researchers from Fox Chase Cancer Center have found that cancerous or precancerous granule neuron precursor cells in the brain express the intermediate filament protein Nestin. Nestin is considered a maker of neural stem and progenitor cells that are present in many types of neurogenic tumors. Activation of Shh signaling pathway is necessary for its expression. Nestin promotes the further activation of the Shh pathway and contributes to tumor progression. It has been found that inflammatory mediators leukotrienes are also crucial for Nestin expression. Consequently, impeding leukotriene synthesis by hindering the biologic activity of enzymes involved in synthesis or blocking leukotriene interaction with its receptors prevents expression of Nestin in cancer cells, which in turn, inhibits their proliferation. This effect is specific to tumor cells, and normal proliferation of healthy cells has not been affected. Inhibitors of leukotriene also prevent glioblastoma cell proliferation.
Thus, inhibition of synthesis or biologic activity of leukotrienes is a novel therapeutic strategy for treatment of Sonic Hedgehog-Associated Medulloblastoma. This strategy is also applicable to Glioblastoma multifirme, the most common tumor of the central nervous system. Notably, leukotriene inhibitors have been already widely used in clinics for treating human asthma, and no severe side effects have been reported.
Li P. et al. Nestin Mediates Hedgehog Pathway Tumorigenesis. Cancer Res. 2016 Sep 15;76(18):5573-83.
US Patent # US 9,616,056 B2
For Licensing/Partnering information, please contact:
Inna Khartchenko, MS, MBA
Director, Technology Transfer
E-mail: [email protected]