Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LH_BETAT_AG retinoblastoma tumors

Samuel K Houston¹, Yolanda Piña¹, Timothy G Murray¹, Hinda Boutrid¹, Colleen Cebulla², Amy C Schefler¹, Wei Shi¹, Magda Celdran¹, William Feuer¹, Jaime Merchan³, Ted J Lampidis^4
1Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; ²Department of Ophthalmology, The Ohio State University, Columbus, OH, USA; ³Division of Hematology/Oncology, Department of Medicine, ⁴Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA

Purpose: The purpose of this study was to evaluate the effect of optimally timed combination treatment with angiogenic and glycolytic inhibitors on tumor burden, hypoxia, and angiogenesis in advanced retinoblastoma tumors.
Methods: LH_BETAT_AG mice (n = 30) were evaluated. Mice were divided into 5 groups (n = 6) and received injections at 16 weeks of age (advanced tumors) with a) saline, b) anecortave acetate (AA), c) 2-deoxyglucose (2-DG), d) AA + 2-DG (1 day post-AA treatment), or e) AA + 2-DG (1 week post-AA treatment). Eyes were enucleated at 21 weeks and tumor sections were analyzed for hypoxia, angiogenesis, and tumor burden.
Results: Eyes treated with 2-DG 1 day post-AA injection showed a 23% (P = 0.03) reduction in tumor burden compared with 2-DG alone and a 61% (P < 0.001) reduction compared with saline-treated eyes. Eyes treated with 2-DG 1 week post-AA injection showed no significant decrease in tumor burden compared with 2-DG alone
(P = 0.21) and a 56% (P < 0.001) decrease in comparison with saline-treated eyes. 2-DG significantly reduced the total density of new blood vessels in tumors by 44% compared to saline controls (P < 0.001), but did not affect the density of mature vasculature.
Conclusions: Combination therapy with angiogenic and glycolytic inhibitors significantly enhanced tumor control. Synergistic effects were shown to be dependent on the temporal course of treatment, emphasizing optimal timing. 2-DG was shown to reduce the density of neovessels, demonstrating an antiangiogenic effect in vivo. As a result, angiogenic and glycolytic inhibitors may have significant potential as alternative therapies for treating children with retinoblastoma.

Keywords: retinoblastoma, adjuvant therapies, angiogenic inhibitors, glycolytic inhibitors