Tumor treating fields suppress tumor cell growth and neurologic decline in models of spinal metastases
Daniel Ledbetter, Romulo Augusto Andrade de Almeida, Xizi Wu, Ariel Naveh, Chirag B. Patel, Queena Gonzalez, Thomas H. Beckham, Robert North, Laurence Rhines, Jing Li, Amol Ghia, David Aten, Claudio Tatsui, Christopher Alvarez-Breckenridge
Daniel Ledbetter, Romulo Augusto Andrade de Almeida, Xizi Wu, Ariel Naveh, Chirag B. Patel, Queena Gonzalez, Thomas H. Beckham, Robert North, Laurence Rhines, Jing Li, Amol Ghia, David Aten, Claudio Tatsui, Christopher Alvarez-Breckenridge
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Resource and Technical Advance Bone biology Neuroscience

Tumor treating fields suppress tumor cell growth and neurologic decline in models of spinal metastases

Abstract

Spinal metastases can result in severe neurologic compromise and decreased overall survival. Despite treatment advances, local disease progression is frequent, highlighting the need for novel therapies. Tumor treating fields (TTFields) impair tumor cell replication and are influenced by properties of surrounding tissue. We hypothesized that bone’s dielectric properties will enhance TTFields-mediated suppression of tumor growth in spinal metastasis models. Computational modeling of TTFields intensity was performed following surgical resection of a spinal metastasis and demonstrated enhanced TTFields intensity within the resected vertebral body. Additionally, luciferase-tagged human KRIB osteosarcoma and A549 lung adenocarcinoma cell lines were cultured in demineralized bone grafts and exposed to TTFields. Following TTFields exposure, the bioluminescence imaging (BLI) signal decreased to 10%–80% of baseline, while control cultures displayed a 4.48- to 9.36-fold increase in signal. Lastly, TTFields were applied in an orthotopic murine model of spinal metastasis. After 21 days of treatment, control mice demonstrated a 5-fold increase in BLI signal compared with TTFields-treated mice. TTFields similarly prevented tumor invasion into the spinal canal and development of neurologic symptoms. Our data suggest that TTFields can be leveraged as a local therapy within minimally conductive bone of spinal metastases. This provides the groundwork for future studies investigating TTFields for patients with treatment-refractory spinal metastases.

Authors

Daniel Ledbetter, Romulo Augusto Andrade de Almeida, Xizi Wu, Ariel Naveh, Chirag B. Patel, Queena Gonzalez, Thomas H. Beckham, Robert North, Laurence Rhines, Jing Li, Amol Ghia, David Aten, Claudio Tatsui, Christopher Alvarez-Breckenridge

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Figure 1

Computational model of TTFields distribution in the human torso with a simulated laminectomy and spinal stabilization for management of spinal tumor.

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Computational model of TTFields distribution in the human torso with a s...
(A) Computational model in axial view, centered at a simulated laminectomy and resection of bilateral pedicles and posterior vertebral body for decompression of the spinal cord. Note that the value of the TTFields intensity was consistently low (<1 V/cm) in regions containing bodily fluids such as chambers of the heart, great vessels, seroma of the resection cavity, and thecal sac (*). The titanium rods are conductive and shunted the electrical field in the surrounding seroma, creating a second adjacent area of minimal field deposition (white closed circles). The residual vertebral body (arrow) retained a higher TTFields intensity (2–3 V/cm), as it has a lower conductivity than that of the surrounding tissue layers. (B) Computational model in axial view at the level adjacent to the tumor resection. At this level, titanium screws were incorporated into the vertebral body and the conductive nature of the metal shunted the electrical field from the seroma and adjacent tissue, thus creating a zone around the implants that have attenuated TTFields intensity (<1 V/cm, dashed circle). However, as the conductive hardware joined the nonconductive bone, it allowed for a greater retention and boost of TTFields intensity (4 V/cm) deposition in the bone (double arrow). Scale bar: 1 cm.