Figure 3

Possible future treatment schedule. A possible complex combination therapy that consists of a cell death inducer and several sensitizer that all target individual components of the PI3K signaling cascade. 1. Take out the cancer cells' ability to move, thus preventing invasion and metastasis, extending the therapeutic window. Continue blocking this arm throughout therapy. 2. Block the DNA repair mechanisms prior to treatment. Importantly do not affect cell cycle progression, thus making cancer cells amenable to most standard treatments. 3. Administer chemo- or radiotherapy. 4. Block the survival pathways mediated by PI3K signaling in the cancer cells stressed by treatment. If, as outlined in Figure 2, details of key mediators are know, e.g. DNA-PK in glioblastoma (4.1), or VDAC1 in neuroblastoma (4.2), target these, otherwise Akt seems the most promising target. 5. Finally, block growth factor receptors to maximize cell cycle arrest, thus preventing a cancer repopulation by the cells that escaped treatment-induced apoptosis. Point 5 might appear superfluous, as 3 and 4 should already block proliferation, however, this inhibition should also target cells that have activated additional signaling cascades or have (epi)genetically escaped sensitivity to treatment.