The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis

PI3K/AKT/mTOR通路 蛋白激酶B 癌症研究 医学 黑色素瘤 PTEN公司 转移 脑转移 肿瘤科
作者
Cedric Tehranian,Laura Fankhauser,Patrick N. Harter,Colin D H Ratcliffe,Pia S. Zeiner,Julia M Messmer,Dirk C Hoffmann,Katharina Frey,Dana Westphal,Michael W. Ronellenfitsch,Erik Sahai,Wolfgang Wick,Matthia A. Karreman,Frank Winkler
出处
期刊:Neuro-oncology [Oxford University Press]
被引量:2
标识
DOI:10.1093/neuonc/noab159
摘要

Background Brain metastases (BM) are a frequent complication of malignant melanoma (MM), with limited treatment options and poor survival. Prevention of BM could be more effective and better tolerated than treating established BM in various conditions. Methods To investigate the temporo-spatial dynamics of PI3K/Akt/mTOR (PAM) pathway activation during BM formation and the preventive potential of its inhibition, in vivo molecular imaging with an Akt biosensor was performed, and long-term intravital multiphoton microscopy through a chronic cranial window in mice. Results In vivo molecular imaging revealed invariable PAM pathway activation during the earliest steps of brain colonization. In order to perform a long-term intravascular arrest and to extravasate, circulating MM cells needed to activate their PAM pathway during this process. However, the PAM pathway was quite heterogeneously activated in established human brain metastases, and its inhibition with the brain-penetrant PAM inhibitor GNE-317 resulted in only modest therapeutic effects in mice. In contrast, giving GNE-317 in preventive schedules that included very low doses effectively reduced growth rate and number of BM in two MM mouse models over time, and led to an overall survival benefit. Longitudinal intravital multiphoton microscopy found that the first, rate-limiting steps of BM formation - permanent intravascular arrest, extravasation, and initial perivascular growth - are most vulnerable to dual PI3K/mTOR inhibition. Conclusion These findings establish a key role of PAM pathway activation for critical steps of early metastatic brain colonization and reveal its pharmacological inhibition as a potent avenue to prevent the formation of clinically relevant BM.
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