BSCI-11. Targeting PI3K/Akt/mTOR pathway to prevent melanoma brain metastasis

Abstract Background Patients developing brain metastasis (BM) still face a poor survival due to limited treatment options. BM prevention using low dose drug schedules could be a more potent strategy with less side effects than treating established BM. This could add a real benefit to the ongoing challenge of facing the frequent BM formation in high-risk malignant melanoma (MM) patients. Methods Aiming to study the dynamics of PI3K/Akt/mTOR (PAM) pathway activation during the brain metastatic cascade, in vivo molecular imaging with an Akt biosensor was performed. Long-term intravital multiphoton microscopy through a chronic cranial window in mice was employed to investigate timing and effectiveness of PAM pathway inhibition for BM prevention. Results In vivo molecular imaging revealed the activation of PAM pathway as a prerequisite for extravasation of circulating MM cells in the brain. However, established human BM present with heterogeneous activation of the PAM pathway. Moreover, in two MM mouse models, PAM pathway inhibition with the brain-penetrant dual PI3K/mTOR inhibitor GNE-317 resulted in only moderate effects on established BM. In contrast, giving low dose GNE-317 in a preventive schedule successfully reduced growth rate and number of BM in both mouse models. Longitudinal intravital multiphoton microscopy suggests that the first, rate-limiting, steps of BM formation can be effectively targeted by dual PI3K/mTOR inhibition. Conclusion PAM pathway activation is key for the critical early steps of MM metastatic brain colonization. These findings reveal that early PAM pathway inhibition is a promising strategy to prevent the formation of clinically relevant BM.