Abstract A109: Repurposing low dose of quinoline methanol derivatives as a novel treatment for pediatric glioblastoma

Abstract

Abstract Both primary brain tumors and secondary brain metastases that start in another part of the body and spreads to the brain, such as lung, breast, melanoma, kidney, nasopharynx, and colon cancers have limited or no response to chemotherapy. Through repurposing drug screen using pediatric glioblastoma cells established from newly diagnosed and recurrent patients, we identified that FDA-approved compound mefloquine have significant cancer killing properties. A growing body of evidence suggests that this extensively used anti-malaria drug may cause adverse neurological effects after crossing the blood-brain barrier and accumulates in the brain at relatively high concentration. To the amelioration of this problem, an analog campaign was conducted in selecting compounds lacking penetration but maintaining the anti-malarial properties using mefloquine as the leading compound. We therefore thought to take advantage of this unique characteristic and use low dose of these compounds and target the infiltrative disease reservoir while avoiding the neurological side effects. While this program focuses on high anti-malaria potency, low neurotoxicity (against rat neurons), and low brain absorption, we are interested in high anti-malaria potency, low general toxicity, and high brain/tumor concentration. Among these compounds, we selected TQM due to its promising results in efficacy, potency, and selectivity in killing brain tumor cells at a much lower range compared to mefloquine based on our quantitative structure-activity relationship model. Studies suggested that this group of drugs induce cell apoptosis in host and parasites through increased production of reactive oxygen species (ROS). Even though for a long time ROS is believed to promote cell proliferation; however, brain cancer cells, due to their high basal metabolic rate, are more susceptible to ROS. Inducing an increased intracellular ROS levels in brain cancer cells may trigger cell death and destroy malignant cells, while sparing normal cells. Our preliminary results confirmed that mefloquine and its derivatives induce apoptosis through autophagy and ROS signaling in brain cancer cells at a much lower concentration, and these compounds reduces tumor growth and extends animal survival in mouse models. Our results pave the way for translation of those compounds to the clinic. Citation Format: Jian Teng, Litia Carvalho, Elie Tabet, Bakhos Tannous. Repurposing low dose of quinoline methanol derivatives as a novel treatment for pediatric glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A109. doi:10.1158/1535-7163.TARG-19-A109