The vast majority of
primary brain tumors derive from glial cells and are collectively called
gliomas. While, they share some genetic mutations with other
cancers, they do present with a unique biology and have developed adaptations to meet specific biological needs. Notably,
glioma growth is physically restricted by the skull, and, unless normal brain cells are destroyed,
tumors cannot expand. To overcome this challenge,
glioma cells release
glutamate which causes excitotoxic death to surrounding neurons, thereby vacating room for
tumor expansion. The released
glutamate also explains peritumoral
seizures which are a common symptom early in the disease.
Glutamate release occurs via system X(c), a
cystine-
glutamate exchanger that releases
glutamate in exchange for
cystine being imported for the synthesis of the cellular
antioxidant GSH. It protects
tumor cells from endogenously produced reactive
oxygen and
nitrogen species but also endows
tumors with an enhanced resistance to radiation- and
chemotherapy. Pre-clinical data demonstrates that pharmacological inhibition of system X(c) causes GSH depletion which slows
tumor growth and curtails
tumor invasion in vivo. An Food and Drug Administration approved drug candidate is currently being introduced into clinical trials for the treatment of
malignant glioma.