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P08.22 Targeting glioblastoma mitochondrial metabolism to inhibit cell proliferation & tumor growth

2017; Oxford University Press; Volume: 19; Issue: suppl_3 Linguagem: Inglês

10.1093/neuonc/nox036.212

1523-5866

T. J. Jue, Sylvia A. Chung, Robert W. Rapkins, Pierre J. Dilda, Philip J. Hogg, Kerrie L. McDonald,

Glioma Diagnosis and Treatment

Background: Abrogating tumor mitochondrial metabolism by targeting the mitochondria and inhibiting the mTOR pathway is an effective mechanism to impede glioblastoma growth. Inhibiting the mitochondrial activity with an organic arsenide compound, PENAO, has been previously shown to decrease oxidative phosphorylation eventuating in the inhibition of glucose metabolism in patient derived glioblastoma cell lines. Temsirolimus, an inhibitor of the mTOR pathway, has also been shown to interfere with glycolysis. We combined PENAO and temsirolimus to determine if the drugs act synergistically to inhibit glioblastoma tumor metabolism and cell proliferation. Methods: In vitro experimentation of PENAO and temsirolimus as single agents, and in combination, were performed on glioblastoma patient-derived cell lines (PDCLs). Both agents were also assessed in vivo using an orthotopic mouse model in which the animals were implanted with the PDCL, RN1. Once tumor growth was confirmed, we randomized the animals into different treatment arms: (i) untreated control; (ii) PENAO alone (3 mg/kg/day); (iii) low dose temsirolimus alone (1mg/kg/day); (iv) high dose temsirolimus alone (5mg/kg/day); (v) combined PENAO and low dose temsirolimus; and (vi) combined PENAO and high dose temsirolimus. Results: A significant synergistic effect on tumor cell growth was observed in vitro using a panel of PDCLs treated with the combination of PENAO and temsirolimus. Apoptosis, measured by FACS analysis for the expression of the marker, Annexin was observed in approximately 90% of the cell population when treated with the combined treatment of PENAO and temsirolimus compared to 25% for PENAO alone and 44% for temsirolimus alone. An orthotopic model was established by intracranially injecting the PDCL, RN1 in balb/c nude mice. Temsirolimus was delivered by gavage while PENAO was continuously administered subcutaneously with an osmotic pump. While high dose temsirolimus alone improved the overall survival times of mice (12-day advantage compared to the control) which is more than what was observed in the combination treatment of PENAO with temsirolimus (5-day advantage compared to control). CONCLUSION: Highly synergistic effects observed in vitro were not translated to the in vivo model. Although the combination of PENAO and temsirolimus was highly effective in PDCLs in vitro, it did not translate into a significant survival improvement in vivo. Ongoing studies have identified that the concentration levels of PENAO crossing the blood brain barrier were inadequate to deliver the synergistic effects observed in vitro. Future studies will investigate mechanisms of enhancing drug delivery of PENAO to the brain.