Delivery of Alternating Electrical Fields Increases Cell Membrane Permeability in Glioblastoma Multiforme

The following article features coverage from the American Association for Cancer Research (AACR) 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Results from a preclinical study of 2 novel approaches for the treatment of glioblastoma multiforme (GBM) evaluated in human GBM cell lines — approaches that include a steroidal lactone natural product and the delivery of alternating electric fields to tumors (tumor treatment fields) — evaluated in human GBM cell lines showed that the former approach inhibited cell growth, and that the 2 approaches worked synergistically, consistent with the increased GBM cell membrane permeability that is associated with the delivery of tumor treating fields. The findings from this study were presented at the American Association for Cancer Research (AACR) Annual Meeting 2019. 

There is a need to develop novel approaches to the treatment of GBM, given the heterogeneity of the disease, the limited effectiveness of current treatments, and the poor prognosis of patients with the disease. Recently, the US Food and Drug Administration (FDA) has approved the delivery of alternating electric fields (ie, tumor treating fields) for the treatment of patients with GBM,² although the mechanism of action of this approach is not well understood. In addition, a steroidal lactone (Withaferin A) extracted from the winter cherry plant, Withania somnifera, and found in the AshwaMAX product, concentrated for Withaferin by up to 4.3%, is another treatment approach under investigation.  

In this study, human GBM cells (GBM2, GBM39, and U87-MG) were isolated from primary tumors and modified to express firefly luciferase. Growth of GBM cells was inhibited by both Withaferin A and AshwaMAX (IC₅₀ ~0.25 µM).  In addition, evidence for synergistic inhibition of cell growth was demonstrated when the steroidal lactone was delivered concurrently with tumor treating fields. Significant differences in cellular membrane permeability (as shown by increased bioluminescence, P <.0001; increased binding and ingress of Dextran-FITC, P <.0001; increased number of membrane holes, P =.0002; and increased sizes of holes in the cellular membrane, P =.0005) were observed when cells exposed to tumor treating fields were compared with unexposed cells.   

“In the present studies, we show that tumor treating fields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics,” the study noted. 

“These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard-of-care strategies,” the researchers noted in conclusion. 

Disclosure: The presenters have disclosed financial ties to Novocure Inc. For a full list of disclosures, please see the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of AACR 2019 meeting by visiting the conference page.

References

1. Chang E, Patel C, Pohling C, et al. Tumor treating fields increases membrane permeability in glioblastoma cells. Presented at: American Association for Cancer Research (AACR) Annual Meeting 2019; March 29–April 3, 2019; Atlanta, GA. Abstract 250/13.
2. Tumor treating fields (Optune). [package insert]. Portsmouth, NH: Novocure Inc.; 2019.