Abstract 5352: Novel treatment approaches in retinoblastoma: Impact of combination therapy on tumor burden

Abstract

Abstract Purpose: The purpose of the current study is to examine vessel targeting, chemotherapy, and mammalian target of rapamycin (mTOR) inhibitor agents in LHBETATAG retinal tumors and their impact on tumor burden. Methods: Group A: Ten-week-old, LHBETATAG mice (n=30) received a single subconjunctival injection of anecortave acetate (AA; 1200, 600, 300, and 150 µg) delivered to right eyes only. Group B: Ten-week-old, LHBETATAG mice (n=30) received a single subconjunctival injection of AA (600, 300, and 150 µg) delivered to right eyes only, either during a cycle of carboplatin (six subconjunctival deliveries) or after the completed cycle. Carboplatin was delivered at the subtherapeutic concentration of 62.5 µg. All animals were euthanatized at 16 weeks of age, and the eyes were examined histopathologically. Group C: Eighteen-week-old, LHBETATAG mice received (n=30) subconjunctival injections of rapamycin once weekly for two consecutive weeks (0.00333, 0.167, 3.33, and 6.67 mg/kg). Tumor sections were analyzed for tumor burden with immunohistochemistry techniques. Results: A statistically significant reduction in tumor burden was detected after a single periocular injection of AA. The reduction of tumor burden followed a U-shaped dose-response curve. Tumor burden was significantly decreased when AA and carboplatin were combined. However, varying doses and delivery schedule of these agents had significant impact on the effectiveness of the combined treatment. The most effective scheme was delivering a low dose (150-300 µg) of AA after a complete cycle of carboplatin. Reduction in tumor burden were 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). Histopathological evaluation showed no signs of retinal toxicity to either treatment used. Conclusions: AA, as monotherapy or as adjuvant therapy, significantly controlled tumor burden in a murine model of retinoblastoma. Moreover, adjuvant therapy enabled the use of typically subtherapeutic carboplatin doses without decreasing efficacy of the therapy. Inhibition of mTOR reduced tumor burden during late disease in the LHBETATAG retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5352. doi:10.1158/1538-7445.AM2011-5352