Optimal therapy for lung and brain cancers using intra- and inter-cellular networks.

Tamaki Wakamoto

Hiroshima University

"Optimal therapy for lung and brain cancers using intra- and inter-cellular networks."

The therapy of cancer is a long-standing and worldwide issue. Since cancers metastasize to other organs, the treatment method of multiple organs simultaneously is required but it is difficult and has not yet been established. In this study, we investigated an optimal therapy method that targets Notch signaling network which shown in multiple cancers in common. As example studies, we targeted embryonal brain tumor (EBT) and non-small cell lung cancer (NSCSC). Both the two cancers undergo oncogenic development through increased HES-1 via Notch signaling, but their signaling pathways of Notch 1 and Notch 2 to enhance HES-1 gene have contrastive roles. In NSCSC, Notch 1/2 activates/inhibits cancerization of cells. In contrast, Notch 1/2 plays an opposite role in EBT, namely, Notch 1/2 inhibits/activates cancerization of cells. To find a possible therapy by which we can treat both cancers at the same time, we developed a conceptual mathematical model based on Notch signaling with the opposite pathways. We explored which network pathway is critical to enhance the cancer cells by sensitivity analysis and found that an intra-cellular pathway is more critical than inter-cellular pathway in enhancing the cancerization of cells and the pathway of Notch transport pathway from cytosol to membrane can be a common network to enhance the cancerization of cells in both cancers. Based on these observations, we also carried out in silico therapy tests for ten patient cases and found that network enhancement therapy is more effective than network cleavage therapy to reduce the number of cancer cells and multiple network therapies are more effective than a treatment of single network therapy. This study suggests that there are optimal signaling network therapies that can treat multiple cancers with contrasting Notch networks and that the simultaneous use of drugs that regulate multiple signaling networks may be most effective in reducing cancer cells.
Additional authors: Michito Ujino (Kyoto University, Faculty of Medicine), Hiroshi Ishii (ASHBi, Kyoto University), S. Seirin-Lee (ASHBi, Kyoto University)

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