Abstract 5802: The impact of tumor-treating fields on cancer stem-like cells isolated from the sub-ventricular zone of glioblastoma patients
Authors: Munoz Yamhilette Licon , Sidebottom Rachel B. , Martinez Frank J. , Varela Samantha , Bowers Christian A. , Piccirillo Sara G.M. 
Published: April 2023

Abstract
Treatment of glioblastoma (GBM) is challenging due to its heterogeneous nature, invasive potential and poor response to standard of care treatments. As a result, GBM inevitably recurs and only approximately 9% of patients survive 5 years post-diagnosis. Areas of residual disease represent the source of the recurrent tumor that is fatal for GBM patients. However, targeting the residual disease is not offered as part of the standard of care because these areas are difficult to identify and, to date, they have not been characterized during disease progression. Our laboratory was the first to identify and characterize residual disease in the sub-ventricular zone (SVZ) of the lateral ventricles of GBM patients. Specifically, we found that in the majority of GBM patients the SVZ is a reservoir of tumor cells that promote therapeutic resistance and seed the recurrent tumor. Specifically, our work revealed that in 65% of the cases the SVZ contains treatment-resistant cancer stem-like cells (CSCs), thus investigating residual disease in this area may hold the key to developing a valid therapeutic target for many patients. In this study, we are examining the impact of Tumor-Treating Fields (TTFields) on treatment-resistant CSCs isolated from the SVZ of GBM patients using molecular techniques, such as single-cell transcriptomics and functional phenotyping analysis. To date, we have isolated and characterized 12 CSCs. These cells are maintained in conditions that preserve the molecular profile of the original patient tumor, thus representing bona fide models to study the impact of TTFields on GBM residual disease. We observed that: (i) CSCs show heterogeneous patterns of response to the alkylating agent Temozolomide (100 µM) and radiation (10 Gy), that mimic the standard of care for GBM patients, (ii) their treatment response is independent of the MGMT promoter methylation status and (iii) the proliferation of CSCs resistant to Temozolomide and radiation is significantly inhibited by TTFields when cells are exposed for 48 hours to the optimized frequency for GBM (200 kHz). Altogether, these findings point to the effectiveness of TTFields following Temozolomide and radiation and set the foundation for the single-cell transcriptomic and functional analysis to elucidate the mechanisms whereby TTFields impact the proliferation of CSCs in the SVZ of GBM patients. In the long run, the results of this work will allow the identification of SVZ-specific targets for the development of novel and more effective treatments for GBM patients.
Citation Format: Yamhilette Licon Munoz, Rachel B. Sidebottom, Frank J. Martinez, Samantha Varela, Christian A. Bowers, Sara G.M. Piccirillo. The impact of tumor-treating fields on cancer stem-like cells isolated from the sub-ventricular zone of glioblastoma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5802.