DRES-11. A SYSTEMS APPROACH FOR DETERMINING THE MECHANISM OF RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA. (5th November 2018)

• Record Type: Journal Article
• Authors: Chen, Dongjiang; Thomas, Nagheme; Le, Son; Deng, Changwang; Jin, Dan; Sebastian, Mathew; Nguyen, Duy; Ren, Jie; Tran, David
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi78
• Page End: vi78
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.318
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite aggressive chemoradiotherapy. Recently, Tumor Treating Fields (TTFields) were approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM. The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules' assembly, leading to disrupted chromosomal segregation and cell death. However, many TTFields responders eventually develop progression. The mechanism of TTFields resistance remains largely unexplored. Understanding how cancer cells gain the ability to circumvent the biophysical forces of TTFields and their downstream effects will provide new opportunities to improve therapeutic efficacy of this novel anti-cancer treatment. To accomplish these objectives, we have developed several human GBM cell lines that demonstrated relative resistance to the cytotoxic effects of TTFields compared to the parental cells. Importantly TTFields-induced chromosomal instability such as the formation of micronuclei was unchanged in resistant cells compared to their sensitive counterparts. In contrast, TTFields-induced inflammatory response was severely suppressed in resistant cells, suggesting that resistance to TTFields may be conferred by a selective loss of the deleterious effects downstream of the biophysical insults. Importantly, this acquired TTFields resistance phenotype of GBM cells was associated with a transition to a stem-like state. Using a systems approach aided by a suite of innovative computational platforms, we methodically dissected this renewed stemness program in resistant cells to identify master regulators of the resistance mechanism. Our long-term goal is to develop targeted therapies that prevent tumor's resistance to TTFields.