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• W2955187879 abstract "Abstract Glioblastoma multiforme (GBM) are the most common and deadly primary brain tumors. GBMs are thought to derive from neuroglial stem or progenitor cells. Although surgery, radiotherapy and concomitant or alternating chemotherapy followed by anti-angiogenic therapy are still the mainstay of treatment, individually tailored strategies based on tumor-intrinsic dominant genomic, transcriptomic, epigenetic and antigenic tumor profiles may ultimately improve outcome. GBM recurrence is thought to be caused by a dynamically changing population of slow-cycling stem-like cells that are capable of evading current therapeutics which spare the radio/chemoresistant cells. Due to the extreme heterogeneity of these tumors, the likelihood of success of new therapeutic strategies for GBM relies on utilizing tailored combinations of targeted genetic-, epigenetic- and/or immune-modulating therapies. Targeting epigenetic polycomb repressor complex 1/2 (PRC1/2) and their key drivers BMI1 and EZH2 is highly attractive to target GBM stem-like and progenitor cells. Since PRC2 activity is dependent on PRC1 chromatin association, targeting BMI1 is a priority for GBM. BMI1 is strongly upregulated in most GBM subtypes, and we and others have demonstrated that reducing BMI1 levels results in a decrease in tumor cell self-renewal and eliminate the stem-cell like phenotypes in other tumor types. We have therefore developed novel small molecule BMI1 inhibitors, named RU-A compounds, for GBM therapy. First, we demonstrate that these RU-A compounds could eliminate BMI1 at low nanomolar conc. We further determined using modeling and luciferase assays that RU-A compounds exert effects on the BMI1 RNA, suggesting that RU-A compounds might bind to a pocket within the BMI1 untranslated region. Strikingly, RU-A compounds demonstrate complete ablation of self-renewal of GBM stem-like cells in serial clonogenic, sphere assays, and GBM organoids, and sensitize GBM cells to chemotherapy. We demonstrate the anti-GBM and reduction of tumor initiation activities of these inhibitors in a series of patient-derived xenografts and patient derived orthotopic mouse models of GBM. Due to the high potency of these compounds, when injected in mice, there were significant reductions in intratumor BMI1 associated with elimination of stem cell-like phenotypes, and no hematopoietic toxicity or neurotoxicity detected. These novel RU-A compounds by altering the stem-like populations of GBM cells offer effective targeted agents that could be utilized alone or combined with other targeted and immune modulatory agents in clinical trials for GBM patients. Citation Format: Michelle Chadwick, Eric Huselid, Monica Bartucci, Michele Patrizii, Kelly Jara, Monal Mehta, John Gilleran, David Augeri, Hatem Sabaawy. Development of novel BMI1 inhibitors targeting glioblastoma stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3073." @default.
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• W2955187879 date "2019-07-01" @default.
• W2955187879 modified "2023-09-27" @default.
• W2955187879 title "Abstract 3073: Development of novel BMI1 inhibitors targeting glioblastoma stem-like cells" @default.
• W2955187879 doi "https://doi.org/10.1158/1538-7445.am2019-3073" @default.
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