Funded Grants

Cell cycle regulation during CNS development by hedgehog signaling and proto-oncogene in n-myc

In the United States, brain cancer is responsible for the deaths of approximately 25,000 patients a year and constitutes the 4th leading cause of cancer-related death. Despite many technological innovations in surgery, radiotherapy and chemotherapy over the past four decades, these tumors remain highly resistant to therapy.

In the field of cancer treatment, a significant event is the development of drugs that can target the specific genetic lesions that define the abnormal biology of cancer cells. An example of this is chronic myelogenous leukemia (CML), a form of a white blood cell cancer that results from a defined genetic mutation. After years of laboratory research, drugs were designed that could counteract the specific effects of this genetic mutation and recent clinical studies have shown this drug to be safe and effective in patients suffering from this disease.

Can a similar strategy be applied to brain tumors? The genetic basis of brain tumor development is poorly understood. A major insight however was the recognition that activating mutations of the "Hedgehog" signal transduction pathway can result in pediatric brain tumor medulloblastoma. In fact, medulloblastoma is the most common solid tumor in children, and typically presents at ages 2-5 yrs. The cancer derives from cells of the cerebellum, a part of the brain involved in movement coordination. While survival is possible in up to 60% of cases, the combination of neurosurgery, chemotherapy, and radiotherapy that is required to save the patient usually results in life long neurological handicap. The need for better drugs designed to counteract the genetic mutations of the Hedgehog pathway are essential to reduce the significant mortality and morbidity associated with medulloblastoma.

In Dr. Rowitch's laboratory, novel genetic targets of Hedgehog signal transduction have been identified using a model of the developing mouse cerebellum. Interestingly, many of the targets identified in this animal model system are expressed in human medulloblastoma. One example of these is N-Myc, a known oncogene. An oncogene can confer properties of a cancer cell. Oncogenes typically are involved in regulation of the cell cycle, which determines whether a cell will divide to produce more daughter cells, or stop dividing and differentiate. Dr. Rowitch's lab has found that N-myc is a gene that is induced and/or activated by Hedgehog signal transduction in the developing cerebellum.

In this research proposal, Dr. Rowitch will identify the way in which Sonic hedgehog works through N-myc to produce proliferation in the developing cerebellum and in cerebellar brain tumors. It is anticipated that the proposed work will identify novel interactions of Hedgehog signaling both within the cell and between cells during development and that it may provide clues for new therapeutic interventions in human tumors.