Suppression of the ‘stemness’ of glioblastoma stem cells

Sharmistha Chakraborty, Daoyan Wei, Peiying Yang
Cancer Res (2022) 82 (12_Supplement): 5075.

Abstract 5075: PBI-05204, a supercritical CO2 extract of Nerium oleander, suppresses the stemness of glioblastoma stem cells and inhibits the Shh-Gli1-NANOG axis

Glioblastoma multiforme (GBM) is an aggressive form of primary brain neoplasm that has a poor prognosis and is resistant to conventional treatment. There is a great need to develop new strategies to improve the outcome of this disease. PBI-05204, a supercritical CO2 Nerium oleander extract containing cardiac glycosides, such as oleandrin, has been tested in Phase I and II clinical trials for treatment of solid tumors. The purpose of the present study was to examine the efficacy of PBI-05204 against GBM and to explore potential mechanisms of action. Rapid growth of GBM has been associated with the presence of pluripotent cancer stem cells that have the capacity of self-renewal, proliferation, and formation of cancer progenitor cells. Genome wide expression profiling of Glioblastoma stem cells (GSCs) demonstrates similarities to embryonic stem cells (ESCs) and progenitor cells defining a pattern of hierarchical appearance of Embryonic stem cell markers: NANOG, SOX2, and GFAP. Using cultures of patient derived GSCs: GBM9 expressing WT EGFR and EGFRVIII, and GS28 expressing EGFR WT, we found that PBI-05204 treatment at concentrations of 0.5, 1 and 2.5 μg/ml for 72 hr significantly inhibited the number of tumor spheres by 59.8, 73.2, and 92.3% in GBM9 GSC, and 47.9, 81.6, and 93.4% in GS28 GSC, respectively. The size of the spheres in PBI-05204 (1 μg/ml) treated GBM9 GSC (103.3 ± 17.5 μm) was also significantly smaller than that of the control group (277.5 ± 10.9 μM, p < 0.01). PBI-05204 treatment significantly inhibited protein expressions of ESCs and progenitor cell markers NANOG, SOX2, and GFAP in a conc-dependent manner in GBM9 and GS28 GSCs as determined by Western blot analyses. NANOG is a transcription factor implicated in the pluripotency of ESCs in various cancers including GBM. Previously it has been shown that the Hedge Hog and Gli axis (HH -Gli) is important for GBM growth, stem cell expansion and establishment of an ESC signature. Western blot analysis showed PBI-05204 down-regulated the expression of Gli1 in both GBM9 and GS 28 GSC after 24 hr. of treatment suggesting it inhibits the Shh-Gli1-NANOG axis. Determination of the antitumor efficacy of PBI-05204 in a GSC derived mouse orthotopic tumor model is currently ongoing and the result will be presented at the meeting. Given that the active components of PBI-05204 have the capacity to readily cross the blood-brain barrier, our findings suggest that this novel botanical drug is a viable candidate that should be considered for treatment of GBM due to its ability to inhibit the stemness of GBM independent of highly resistant EGFR/EGFR VIII mark.

Citation Format: Sharmistha Chakraborty, Daoyan Wei, Peiying Yang. PBI-05204, a supercritical CO2 extract of Nerium oleander, suppresses the stemness of glioblastoma stem cells and inhibits the Shh-Gli1-NANOG axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5075.

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