Abstract 2171: Efficacy of chemotherapeutic agents in brain metastases of lung cancer model

Abstract

Abstract Background: Lung cancer is not only the second most common cancer in the United States, but it is also the highest cause of cancer-related death worldwide. In 2017, it is estimated that there will be over 200,000 new cases and 150,000 deaths as a result of lung cancer. The associated high mortality can in part be attributed to the high rate of primary lung cancer metastasis to the brain. Median survival for untreated patients with metastatic brain lesions is approximately 4 to 9 months, while treated patients still typically die within two years. Treatment options are limited for patients with brain metastases due in part to chemotherapeutic ineffectiveness, as many agents used to treat the primary tumor are not able to penetrate the blood-brain barrier (BBB). This study aims to investigate the efficacy of various chemotherapies on brain metastases of lung cancer via bioluminescence imaging data as a surrogate for tumor burden and overall survival data. Methods: Female athymic nude mice underwent intracardiac injection with brain-seeking PC-9 lung cancer cells transfected with Luc-2 and TdTomato. Tumor burden was monitored using bioluminescent imaging biweekly. Upon tumor burden establishment, mice were administered either Doxil (peglylated liposomal doxorubicin) (6 mg/kg), irinotecan (50 mg/kg), gemcitabine (60 mg/kg), docetaxel (10 mg/kg), eribulin (1.5 mg/kg), vinorelbine (10 mg/kg), cisplatin (5 mg/kg) + etoposide (10 mg/kg), cisplatin (5 mg/kg) + pemetrexed (100 mg/kg), osimertinib (25 mg/kg), or gefitinib (6.25 mg/kg). Upon sacrifice, brains were perfused to visualize tumors and permeability using fluorescent microscopy. Survival data were collected and plotted on a Kaplan-Meier curve for statistical analyses. Results: Bioluminescence for nontargeted chemotherapy was nearly equal to that of vehicle. Osimertinib (25 mg/kg) demonstrated immediate decreased tumor burden and increased survival. Vehicle and all nontargeted agents had a survival of 42 +/- 3 days. Images taken of metastatic lesions indicate permeability has increased compared to normal brain, but is not as drastic as expected (1.5 to 1.8 fold increase) and displays heterogeneity between tumors. Conclusion: The efficacy of chemotherapies in brain metastases of lung cancer is not necessarily associated with increased permeability. No smaller nontargeted agent showed improved survival or superior tumor control compared to vehicle, while the third-generation EGFR inhibitor osimertinib showed superior tumor burden control and survival in vivo. Future directions aim to investigate methods to increase drug permeation into tumors so that they may overcome the BBB and accumulate to cytotoxic levels in tumors. Citation Format: Rachel M. Tallman, Neal Shah, Sam Sprowls, Mark Pinti, Afroz Mohammad, Paul Lockman, Pushkar Saralkar. Efficacy of chemotherapeutic agents in brain metastases of lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2171.