Gliomas, the most common type of primary brain tumors, constitute a significant cause of epilepsy, particularly among the elderly. Current standard treatment, surgical resection followed by radiotherapy and chemotherapy with temozolomide, merely provides a limited increase of median survival. As the leading presenting symptom of malignant brain tumors, seizures often recur and aggravate during the course of illness. Despite the high frequency of incidence, seizures caused by gliomas are poorly managed, as nearly 50% of patients show resistance to current antiepileptic drugs (AEDs) and status epilepticus (SE) has been reported in more than 10% of all malignant glioma cases. Refractory epilepsy represents a major impediment to tumor management; therefore, there is a dire need for new therapies with sufficient efficacy for glioma patients who also suffer from uncontrollable seizures. However, the molecular mechanisms of epileptogenesis in malignant tumor-bearing brains are poorly understood. Recent evidence suggests that cyclooxygenase-2 (COX-2), a likely contributor to some forms of acquired epilepsy, might be involved in the development of malignant gliomas via producing prostaglandin E2 (PGE2). We show that PGE2 facilitates tumor cell proliferation, invasion and inflammation largely through the G?s-coupled EP2 receptor, and that activation of EP2 aggravates neuronal inflammation and degeneration after prolonged seizures in epileptic rodents. Our main hypothesis is that blocking the inflammatory prostaglandin receptor EP2 will impair the development of gliomas and thus suppress the concomitant seizures. To test this hypothesis, we will use a combination of pharmacological and genetic approaches to delineate the PGE2/EP2 signaling-mediated inflammation in human malignant glioma cells (Aim 1), and to determine the effects of EP2 receptor inhibition on the development of spontaneous seizures associated with malignant gliomas (Aim 2). Successful completion of this project will lead to the identification of novel molecular targets for the prevention and/or modification strategy for malignant gliomas and the concomitant epilepsy.
As the most common and lethal of primary brain tumors, malignant glioma is a leading cause of epilepsy among the elderly, yet it lacks satisfactory treatment. As another very unfortunate fact, the current antiepileptic drugs fail to control seizures in nearly half of glioma patients. Developing novel therapeutics for malignant glioma and associated epilepsy is an urgent unmet need. The work proposed here will delineate a signaling pathway that might be essential to the development of both malignant glioma and epileptic seizures, and could lead to a novel strategy to prevent brain tumor-associated epilepsy.
