Glutamate Receptor as a Therapeutic Target in Recurrent Glioma: Patient-Derived Glioma Xenograft Model

Glioma is the most common primary brain tumors, whereas the treatment of choice remains with surgery, radiotherapy and chemotherapy. Even though breakthroughs have been made, but the obstacle of Temozolomide(TMZ) side effects and tumor recurrence is yet to be overcome, leaving the breakthrough of glioma treatment in a dilemma. Recent studies suggest that the presence of brain tumor stem cells is highly associated with the development of drug-resistance in tumor cells as well as tumor recurrence. Therefore, intoxicating or inhibition of the drug-resistant cells and brain tumor stem cells became an area of interest for medical professionals, aiming to improve the survival rate of brain tumor patients. Clinicians and scientists have been attempting to develop new treatment options by designing new drugs or using combination of various drugs, hoping to achieve a more efficient way to destroy brain tumor stem cells and drug-resistant cells. Our preliminary studies have discovered that fluoxetine (Prozac), a drug used in treating depression is capable of switching on the glutamate receptor on the surface of tumor cells, generating excitotoxicity with high specificity to target and destroy brain tumor cells. Our preliminary results also confirmed that stem cells-like glioma cells and TMZ-resistant tumor cells express even more glutamate receptors than original glioma cells; moreover death of the TMZ-resistant cell can be achieved by giving Prozac with doses in the safety margin. Other than above stated, Prozac in addition with low dose of TMZ can destroy even more brain tumor cells, creating a synergistic effect. Significant breakthrough in treating and preventing the recurrence of brain tumors may be achieved via the combination of TMZ with Prozac or other glutamate receptor modulators; as this may reduce the chemo-therapeutic dose of TMZ, decreasing TMZ’s side effect, but still effective in exicitotoxicating brain tumor stem cell and TMZ-resistant cells. Our study aims to understand more regarding the toxicity and mechanism of action in combination of TMZ and Prozac (or other glutamate receptor modulators). We will also conduct clinical trials to assess the possibility of using TMZ-Prozac combined drugs as a new therapy in treating brain tumors. Objectives of this three-year research project are as follow: Year-one: We will use the cell lines and primary culture of glioma cells, and then assess the toxicity effect as well as the mechanism of action in combined therapy toward brain tumor stem cell and TMZ-resistant cells. Year-two: We will direct animal studies and patient-derived xenograft model as pre-clinical trials, assessing the effect of combination therapy toward tumor growth and its impact toward drug-resistant tumors. Year-three: Hold a collaboration of the neurosurgery departments in the Taipei Medical University affiliated hospitals, human trials will be conducted to understand the efficacy of combined therapy in patients with glioma.