Principal Investigator: Michael K. Cooper, MD, Vanderbilt University Medical Center, Nashville, Tennessee

The intractable nature of gliomas to current chemotherapies and radiation underscores a tremendous need for improved interventions. A recent advancement in our understanding of malignancies have been the identification of a rather small population of cancer cells that are critical for maintaining the growth of the entire tumor. These cancer stem cells appear to be resistant to the conventional chemotherapy and radiation treatments. However, another major advancement has been the recognition that some of the same signaling pathways that regulate the growth of the stem cells during embryonic development also regulate cancer stem cells.

One of these developmental pathways is called the Hedgehog signaling pathway. In malignancies of the skin, lung and intestine for example, it has been demonstrated that Hedgehog signaling is required for their growth. In our previous work, we have identified compounds that inhibit Hedgehog signaling and determined that the Hedgehog pathway is activated in stem cells in some types of adult gliomas. Thus the inhibition of Hedgehog signaling in certain glioma subtypes may target a critical tumor cell population in a pathway-specific manner.

In this proposal, we seek to better define the pediatric glioma subtypes in which the Hedgehog pathway is activated and to determine whether the delivery of Hedgehog inhibitors will halt the growth of these human gliomas in an animal model. If successful, these preclinical findings will constitute an important component for developing a novel therapeutic strategy for malignant gliomas and a basis for patient selection.