Specific key proteins inhibit an important metabolic driver that plays an important role and enables new cancer therapy for brain developmental disorders. Scientists from the German Cancer Research Center (DKFZ) and the University of Innsbruck, together with a Europe-wide research network, have discovered a molecular mechanism. In addition, this approach could create new opportunities for personalizedTreatment of cancer diseasesand neuronal disorders.
Pathways for new cancer therapy and treatment of epilepsy in sight
The signaling protein called MTOR (Mechanistic Target of Rapamycin) is a sensor for nutrients such as amino acids and sugars. When enough nutrients are available, MTOR boosts metabolism and ensures that sufficient energy and cellular building blocks are available. Since MTOR is a central switch for metabolism, errors in its activation lead to serious diseases. Cancer and developmental disorders of the nervous system, leading to behavioral problems and epilepsy, can result from such a malfunction. The cell therefore controls the activity of this key protein very precisely with the help of so-called suppressors. These are molecules that inhibit such a protein and help regulate its activity. The TSC complex is one such suppressor of MTOR. It is named after the disease that causes its absence – tuberculosis (TSC). The TSC complex, along with MTOR, is located on small structures in the cell called lysosomes, where it keeps MTOR in check.
For example, if the TSC complex no longer remains on the lysosome due to changes in one of its components, this can lead to serious health consequences. The researchers therefore examined how the TSC complex binds to lysosomes. They discovered that the G3BP proteins are located on lysosomes along with the TSC complex. There, the G3BP proteins form an anchor that ensures that the TSC complex can bind to the lysosomes, according to the study authors. This anchoring function plays a crucial role in breast cancer cells. When the amount of G3BP proteins is reduced in cell cultures, it not only leads to increased MTOR activity but also increases cell migration. Drugs that inhibit MTOR prevent this spread, as the researchers were able to show in cell cultures.
Potential therapeutic approach
In breast cancer patients, low G3BP levels correlate with a worse prognosis. Biomarkers such as the G3BP proteins could be helpful in personalizing therapies based on inhibiting MTOR, said Kathrin Thedieck, professor of biochemistry at the University of Innsbruck. The good thing is that drugs that inhibit MTOR are already approved as cancer drugs and could be specifically tested in further studies. G3BP proteins also inhibit MTOR in the brain. In zebrafish, an important animal model, the researchers observed disruptions in brain development when G3BP is missing. This leads to neuronal hyperactivity similar to epilepsy in humans. These neuronal discharges could be suppressed by drugs that inhibit MTOR. The authorsthis studytherefore hope that patients with rare hereditary neurological diseases in which dysfunction of the G3BP proteins play a role can benefit from drugs against MTOR. In the future, the scientists want to investigate this together with their Europe-wide research network.
