Abstract 2945: Arsenic trioxide sensitizes glioma stem cells to brain penetrant PI3K and mTOR inhibitor GDC-0084 Academic Article uri icon

abstract

  • Abstract Glioblastoma is the most aggressive primary malignant brain tumor with few effective therapies. The current study evaluated arsenic trioxide (As2O3, ATO), a small-molecular agent that inhibits tumor growth via promoting promyelocytic leukemia protein (PML) degradation, in combination with multiple PI3K/mTOR inhibitors using high-throughput screening (HTS) to validate if ATO reverses glioblastoma resistance to PI3K/mTOR-targeted therapy. Quantitative single-agent and 2-drug combinations (5 drug doses, maximal concentration of 1 uM of each agent) were evaluated in 20 patient-derived glioma stem-like cells (GSCs). ATO was applied as an anchor drug and several mTOR and EGFR inhibitors as probe drugs to explore potential combination efficacy. Data from single-agent screening demonstrated that brain penetrant PI3K/mTOR inhibitor GDC-0084 potently inhibited cell viability with an IC50 ranging from 0.12M to 5.78M under normoxic conditions. Under hypoxic conditions, 10 of the 16 GSC cell lines remained sensitive, indicating less efficacy of GDC-0084 in the setting of a hypoxic microenvironment. Evaluation of drug combinations identified ATO and GDC-0084 as the most effective combination in vitro. ATO was synergistic with GDC-0084 in several GSCs resistant to GDC-0084 monotherapy. GSC sensitivity to GDC-0084 as single agent and in combination correlated with apoptosis, angiogenesis and PI3K/Akt pathways using gene set enrichment analyses (GSEA). In vitro combination treatment significantly inhibited PML, p-S6, p-AKT and p-mTOR expressions compared to single agent. In an orthotopic mouse model of glioma, targeting PI3K/mTOR with GDC-0084 prolonged the median survival to 81 days compared to 69 days in the control group. The efficacy of combining ATO and GDC-0084 in an orthotopic GSC mouse model is ongoing. Our studies confirm prior work demonstrating the efficacy of combining GDC-0084 with ATO, which now requires clinical validation. Citation Format: Jianwen Dong, Emmanuel Martinez-Ledesma, Nghi Nguyen, Caroline Carrillo, Yuji Piao, Verlene Henry, Soon Young Park, Ningyi Tiao, Clifford Stephan, Roel Verhaak, Erik Sulman, Veerakumar Balasubramaniyan, John F. de Groot. Arsenic trioxide sensitizes glioma stem cells to brain penetrant PI3K and mTOR inhibitor GDC-0084 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2945.

published proceedings

  • Cancer Research

author list (cited authors)

  • Dong, J., Martinez-Ledesma, E., Nguyen, N., Carrillo, C., Piao, Y., Henry, V., ... Groot, J.

citation count

  • 1

complete list of authors

  • Dong, Jianwen||Martinez-Ledesma, Emmanuel||Nguyen, Nghi||Carrillo, Caroline||Piao, Yuji||Henry, Verlene||Park, Soon Young||Tiao, Ningyi||Stephan, Clifford||Verhaak, Roel||Sulman, Erik||Balasubramaniyan, Veerakumar||Groot, John F de

publication date

  • January 2018