Abstract 5504: Development of screening system for Brain Tumor Stem Cell-targeting chemotherapeutic agents

Abstract

Abstract Introduction: Malignant glioma remains one of the most devastating diseases despite recent advances in therapies. Standard of care for malignant gliomas consists of maximal surgical resection, followed by external radiation with concurrent chemotherapy with temozolomide. Unfortunately, tumor recurrence is essentially inevitable and most of the therapies have only limited effects on the survival of patients experiencing tumor recurrence or progression. Emerging evidence has indicated that Brain Tumor Stem Cells (BTSC) can be the specific target of therapy and that elimination of BTSC will most likely result in the growth arrest of the entire tumor mass and the prevention of recurrence. The current therapies, however, preferentially target non-stem tumor cells. Thus, identification of BTSC-specific drugs is highly recommended in order to eradicate the entire tumor cells. To discover the prospective compounds from a large number of candidates efficiently, we have developed here the screening system for BTSC-targeting chemotherapeutic agents. Candidate compounds are screened in a stepwise manner based on their inhibitory potential against BTSC by using several in vitro and in vivo preclinical assays. Being different from the conventional compound discovery procedure, we combine multiple assays aiming at detection of the drugs directly targeting BTSC. Thus, this system functions as a rational agent-prioritization process essential for future progress in developing effective novel cancer treatments. Experimental Approach: We use several human BTSC cultures derived from surgical specimens. These samples have been confirmed to be clonogenic and multipotent in culture, and tumorigenic by xenotransplantation in immunodeficient mice brains. To assess the effect of compounds, the initial step is to use clonogenic assay, cell survival and migration assays with slice cultures of mouse brains, and xenotransplantation of pretreated BTSC. Potential compounds are then processed to the in vivo efficiency and efficacy validation assays using the following animal models, 1. BTSC-derived mouse brain tumor model: patient-derived BTSC transplanted in the mouse brain, 2. Genetically-engineered spontaneous mouse brain tumor model, and 3. Subcutaneous xenograft model of surgical specimens of brain tumor tissues: tumor tissue from patient directly transplanted subcutaneously into immunodeficient mice. Effect of the treatment on tumor progression is monitored by several imaging modalities including microMRI, SPECT/CT, and PET/CT. We also carry out pharmacokinetics profiling to determine the serum levels of the tested compounds and the maximum tolerated dose evaluation to determine their toxicities in comparison to their antitumor activities. In this presentation, we describe the strengths and limitations of each of our assays and also our data with the leading compounds from the previous screening. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5504.