Abstract B023: Targeting therapy induced senescence with small molecule Protein Phosphatase 2A (PP2A) activators to prevent glioblastoma relapse after first line treatment

Abstract Glioblastoma (GBM) accounts for 60-70% of high-grade brain tumors and they are the most common primary brain tumor type in adults. GBM affects 3.2 in 100,000 people who have an average survival time of around 15 months after presentation. Current standard of care for GBM relies on maximal safe resection of the tumor, followed by concomitant treatment with radiation therapy (XRT) and temozolomide (TMZ). TMZ is a DNA methylating agent and induces DNA double strand breaks and it inhibits tumor cell proliferation. The current standard of care is effective in the sense that it provides respite from disease progression for 12 to 18 months and because of this XRT and TMZ are likely to remain first-line therapy for the foreseeable future. However, disease relapse is near universal, >95%, with patient survival rates below 10% five years after diagnosis. It has become apparent that the major effect of TMZ is to induce cellular senescence in GBM with only about 20% cell killing versus 80% stably senescent, TMZ resistant, tumor cells in vitro. XRT also induces significant GBM tumor cell senescence comparable way to TMZ. This effect is termed therapy induced senescence (TIS). TIS by DNA damaging agents has positive effects early in the treatment of cancer: stable cell cycle arrest halts tumor growth, as well as activating immune surveillance, which does translate into temporary clinical benefit in the context of GBM. However, senescent cancer cells remain after initial treatment as a population which undergoes further mutation and metabolic reprogramming to promote an aggressive proliferative, and often metastatic, relapse GBM phenotype which is invariably fatal. Senescent cells undergo changes, including acquisition of a senescence-associated secretory phenotype (SASP). SASP creates conditions conducive to tumor growth and metastasis when quasi-senescent cancer cells, or cancer stem cells, reacquire a proliferative phenotype. Considering established first-line GBM therapy, any new compound will most readily be introduced if it can be introduced in TMZ and XRT treated patients with a view to delaying or preventing GBM relapse. We present preliminary data on our lead PP2A activator ATUX-1215 as a senotherapeutic for TIS-GBM in vitro, where tumor cell senescence was induced with TMZ. ATUX-1215 is senolytic in TIS-GBM by inhibition of pro-survival MEK-ERK (MAPK) kinase signaling and by suppression of anti-apoptotic Bcl-2 family proteins, will cell death by apoptosis as judged by dose dependent caspase-3/7 induction. Further we present data on senomorphic effects of ATUX-1215 in TIS-GBM with reduced expression of SASP proteins, prominently CCL2 and PAI-1, in TMZ treated (senescent) tumor cells versus treatment naïve (proliferating) tumor cells. Thus, PP2A activation by ATUX-1215 simultaneously addresses both aspects underlying tumor relapse in TIS-GBM and the therapeutic modality addresses head-on the clinical reality that new GBM therapies will have to be effective in first line TMZ and XRT treated patients. Citation Format: Johana T. Ohlmeyer, Muhammad Sheraz, Elizabeth A. Beierle, Michael Ohlmeyer. Targeting therapy induced senescence with small molecule Protein Phosphatase 2A (PP2A) activators to prevent glioblastoma relapse after first line treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B023.