EXTH-33. TO ACHIEVE GREATER EFFICACY IN TUMOR-TREATMENT FIELDS: MODELING BASED ON THE INTRACELLULAR MECHANISMS

Abstract

AbstractDespite invasive surgical resection of glioblastoma followed by radiotherapy and/or chemotherapy with concomitant side effects, most patients survive just 1 to 2 years, with no improvement in survival rates in over a decade. In contrast, low-intensity, alternating electric fields delivered non-invasively via scalp electrodes (tumor-treating fields, ‘TTFields’) lack side effects and combined with chemotherapy significantly increase glioblastoma patients’ survival without affecting quality of life. TTFields are in clinical trials for non-small lung cell, pancreatic, and ovarian cancers. To identify TTFields’ mechanisms, improve efficacy, and expand side-effect-free application to more cancer cell types we have built multi-purpose finite element models in COMSOL of TTFields’ effect on critical sub-cellular structures. It is well-established that TTFields interfere with rapidly-dividing cells’ mitotic processes, causing abnormal chromosome segregation, aneuploidy, and apoptosis, probably through multiple mechanisms. The sub-cellular targets of TTFields are likely high dipole-moment and polarizable molecules such as microtubules (MT) and septin, whose unperturbed functioning are critical to silencing cell cycle checkpoints and normal progression of mitosis. Our models allow quantitative investigation of physical interactions between the electric field and these structures, thereby gaining deep insight into the biophysics of TTFields. The models have revealed electric field amplification at MT ends, high current and high energy density in the counter-ion layers surrounding MT C-termini thought to be the critical MT signaling mechanism. These findings support TTFields’ reported mechanisms of action. We are currently testing mechanistic hypotheses posed by TTFields research teams, including: 1. Dislocalization of septins causing aberrant mitotic exit; 2. Mitotic spindle disruption leading to improper chromosome segregation and mitotic catastrophe; 3. Disruption of MT polymerization homeostasis. We encourage researchers to send us their hypotheses to test in our modeling.