A common and serious complication of malignant melanoma is the development of brain metastases. Systemic therapies can prolong survival but do not reach tumor cells in the brain. A potential therapeutic target could be the PI3K/Akt/mTOR pathway.
Therapeutic options for brain metastases of malignant melanoma have been very limited. PI3K/Akt/mTOR (PAM) pathway inhibition was therefore a consideration, as this is specifically upregulated in brain metastases. In addition, this method has already resulted in a reduction of macrometastatic growth and regression of micrometastases. For the study, longitudinal in vivo two-photon microscopy was performed through a chronic cranial window. In addition, in vivo molecular microscopy, fluorescence microscopy, and bioluminescence measurement in mice were used. The observations showed a stable and long-lasting activation, which is already necessary for extravasation and further brain metastasis formation in early intravascular arrest of tumor cells in brain vessels. After brain colonization, tumor cells showed stable activation of the pathway, which was reduced upon administration of dual PI3k/Akt inhibitor GNE-317. Preemptive administration of low-dose GNE-317 then indeed resulted in a lower burden of brain metastases and increased overall survival compared with higher-dose treatment of established metastases or a control group. Using molecular microscopy, this study was able to demonstrate the important role of the PAM pathway in the development of brain metastases as well as to prove PI3k/mTOR inhibition as a preventive measure. Thus, low-dose PI3k/mTOR inhibition represents a new anti-metastatic therapeutic option for advanced malignant melanoma.
Source: Tehranian C, et al: Inhibition of the PI3K/Akt/mTOR pathway as a prevention concept against brain metastases of melanoma. Poster presentation at DGN 2021; Poster: EP108.
InFo NEUROLOGY & PSYCHIATRY 2021; 19(6): 34.
