Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors

Abstract

Purpose:The purpose of this study is to analyze the dose response of the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, on tumor burden and hypoxia, and study the treatment effect on vasculature in LHBETATAG retinal tumors.Methods:This study was approved by the Institutional Animal Care and Use Committee and follows Association for Research in Vision and Ophthalmology guidelines. Eighteen-week-old LHBETATAG retinal tumor eyes (n = 30) were evaluated. Mice were divided into five groups and received periocular injections once weekly for two consecutive weeks of: a) 80% DMSO (dimethyl sulfoxide, vehicle control), b) 0.00333 mg/kg, c) 0.167 mg/kg, d) 3.33 mg/kg, and e) 6.67 mg/kg of rapamycin. Tumor sections were analyzed for hypoxia, tumor burden, and vasculature with immunohistochemistry techniques.Results:Reduction in tumor burden and hypoxia was significantly different between rapamycin doses and control (P < 0.002). Eyes treated with rapamycin at 0.167, 3.33, and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (P = 0.019, P = 0.001, P = 0.009, respectively) and the 0.00333 mg/kg dose response (P = 0.023, P = 0.001, P = 0.010, respectively). Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively). The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means). The number of neovessels was not significantly different between both groups (P = 0.092).Conclusion:Inhibition of mTOR was shown to reduce tumor burden, hypoxia, and vasculature in the LHBETATAG retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.

Rosacea Blepharoconjunctivitis Treated with a Novel Preparation of Dilute Povidone Iodine and Dimethylsulfoxide: a Case Report and Review of the Literature

“…The authors found that 90% and 100% DMSO worsened ocular inflammation, while doses lower than 30% demonstrated anti-inflammatory properties [ 30 ]. Other studies conducted in 2010 and 2011 saw its administration both subconjunctivally and following trabeculotomy [ 31 , 32 ]. A synopsis of published DMSO ocular findings is detailed in Table 1 .…”

Overexpression of Biglycan is Associated with Resistance to Rapamycin in Human WERI-Rb-1 Retinoblastoma Cells by Inducing the Activation of the Phosphatidylinositol 3-Kinases (PI3K)/Akt/Nuclear Factor kappa B (NF-κB) Signaling Pathway

“…Rapamycin is a chemotherapy agent used in the treatment of RB [28,29]. This study aimed to investigate the effects of overexpression of the BGN gene in WERI-Rb-1 human RB cells including the response to rapamycin.…”

“…This finding is of particular interest, as a recent report showed that the PI3K/Akt/mTOR pathway was dysregulated in human RB [8]. As an inhibitor of mTOR, rapamycin has particular cytotoxic effects on hypoxic cell populations [28,29]. The findings of the present study also showed that inhibition of the PI3K/Akt/mTOR pathway suppressed the activation of NF-κB signaling by increasing the cytoplasmic of IκBα and reducing cell nuclear expression levels of p65.…”

Retinoblastoma treatment: impact of the glycolytic inhibitor 2-deoxy-d-glucose on molecular genomics expression in LHBETATAG retinal tumors

“…A combination therapy that targets both pericytes and angiogenesis has been shown to cause a higher percentage of tumor burden and vasculature decrease 53. Also, the low O 2 -sensitive mTOR that stimulates cellular metabolism and angiogenesis through the upregulation of HIF26 was found to decrease tumor burden by both decreasing intratumoral hypoxia and mature blood vessels 55…”

“… 53 Also, the low O 2 -sensitive mTOR that stimulates cellular metabolism and angiogenesis through the upregulation of HIF 26 was found to decrease tumor burden by both decreasing intratumoral hypoxia and mature blood vessels. 55 …”