Evaluation of the Effects of Selective Serotonin Reuptake Inhibitor on High Grade Glioma

The incidence of primary brain tumors worldwide is approximately 7 per 100,000 individuals per year, accounting for 2% of all primary tumors. Approximately 18,000 people in the United States are diagnosed each year with a malignant primary brain tumor. Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor in adults and accounts for about 50% to 60% of cases. The median survival of glioblastoma patients is approximately 12 months. The poor prognosis of GBM has been shown to be affected by multiple factors, both preoperative clinical characteristics and therapeutic characteristics such as quality of surgery, radiotherapy and chemotherapy. Efficacy of the chemotherapy is often impeded by insufficient drug delivery across the Blood-Brain-Barrier (BBB). Nearly 98% of small molecules and 100% of large molecules are prevented from being up taken by BBB. Unfortunately, limited medications which are able to pass through the BBB cannot discern efficiently between healthy and cancerous cells, thus causing side effects. A drug which can pass through BBB and selectively kill brain tumor cells has been highly anticipated. The selective serotonin reuptake inhibitor (SSRI) antidepressants have recently been reported to specifically kill malignant cells. A previous epidemiologic study reported a 30% reduced risk of colorectal cancer among users of high doses of SSRIs. Accordingly, SSRIs have been proposed as lead compounds in the development of new approaches to the treatment of leukemia or other cancers. However, the therapeutic potential of SSRI for the treatment of GBM and the molecular mechanism underlying SSRI-induced cancer cell death remains unclear. Here we attempted to explore the therapeutic potential of SSRI in the treatment of GBM and to dissect the underlying signaling pathways of SSRI induced cell death. The aims of this three-year project are: Aims-1st year: (1) Validation of the survival time in GBM patients with or without SSRI treatment from the National Health Insurance Research Database. (2) Screening for the potential SSRI antidepressant drug candidate to suppress GBM. Aims-2ed year: (1) In vitro studies to understand the mechanisms of SSRI induced cell death. (2) In vivo studies to conform the therapeutic potential of SSRI in GBM.Aims-3rd year: (1) Verification of cell surface receptors of SSRI in GBM patients.(2) Phase II clinical trials of potential SSRI in GBM patients.