Numerous human cancers including radio-resistant human glioblastomas require a constitutive activation of the PI3K-Akt pathway for their survival. In this context the protein phosphatase-2A (PP2A) family of ser/thr protein phosphatases is a central regulator of cell homeostasis that counteracts the aberrant oncogenic PI3K survival signal. Importantly the trimeric ABαC holoenzyme, named PP2A₁, specifically counteracts the aberrant oncogenic constitutively activated PI3K survival signal. In this regard we recently reported that the pharmacological activation of PP2A mediated by the sphingolipid analog FTY720 down-regulated the constitutively active PI3K/Akt pathway involved in the survival of radio-resistant U87G human glioblastoma cells. In this study, using a peptide-based drug phosphatase technology (DPT) we rational designed a new PP2A activator corresponding to an ApoE-mimetic bipartite-peptide, named DPT-Cog, that combines the cellular inactive DPT-sh1 shuttle (VKKKKIKREIKI) and the PP2A activating COG133 sequence (LRVRLASHLRK LRKRLL). We first demonstrated that this new chimeric DPT-sequence down-regulated the PI3K-Akt survival pathway and inhibited the survival of U87G cells. In addition we found that DPT-Cog decreased the growth of human glioblastoma U87G cells. Furthermore, DPT-Cog also decreased the growth of X-irradiated U87G senescent cells. In conclusion we characterized the DPT-Cog molecule, a new ApoE cog-mimetic and potential anti-tumor peptide. Our results clearly indicate that DPT-Cog counteracted PI3K survival pathways of U87G cells and is also toxic against irradiated U87G senescent cells.