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Michael Marand
For decades, cancer therapy has been dominated by surgical resection, radiation therapy, and chemotherapy. But each of these methods comes with its limitations. Surgery fails when there are scattered, small bits of tumor that escape to other areas of the body, called metastases. Radiation therapy fails when said metastases are not large enough to be seen with imaging technology. Chemotherapy only exists for certain types of cancers. And when it comes to brain cancer, the body throws chemotherapy another obstacle: the blood brain barrier (BBB). The BBB is the body’s mechanism for preventing pathogens from being transferred from the blood to the fluid of the brain. While the BBB serves the vital function of protecting this precious organ, it also means that many systemically administered chemotherapy drugs will often not be allowed to reach brain tumors and do their job.
New methods have been developed to supplement existing surgery, chemotherapy, and radiation therapy treatments. These methods aim to improve shortcomings in specificity, safety, and universality. Clinicians are hopeful that these novel methods will be better at seeking out cancerous cells in the body and attacking them. Ideally, these methods will leave healthy cells untouched and increase the range of treatment options for certain types of cancer. Some of these methods include nanoparticles, cell-based therapies, and electric fields. Admittedly, one of the aforementioned may sound more like science-fiction than reservedly science. Sure, you once learned about how rubbing a balloon can make it stick to the wall, but what do electric fields have to do with cancer treatment?
Electric fields are useful in retarding the growth of glioblastoma. Glioblastoma, considered the most aggressive kind of brain tumor, has a five-year survival rate of only slightly above 5%. Glioblastoma is also the most commonly occurring primary malignant brain tumor, making up 65% of all brain tumor cases. Since its introduction by Novocure in 2017, Optune System has been offered as a treatment option to patients 22 years or older suffering from glioblastoma. The treatment works by administering low-intensity, wave-like electric fields from a wearable device attached to a patient’s scalp.
The electric fields administered by Optune work in two main ways to combat cancerous cell growth. The first way is by preventing the formation of microtubules, which are responsible for pulling duplicated genetic material to opposite poles of a dividing cell. While the cell is in a spherical shape, electric fields administered by Optune pass through the cell uniformly. The building blocks of microtubules get caught in this uniform field and flip-flop back and forth, as if they are objects stuck in a wind tunnel that keeps alternating the side of pressure. These building blocks are not able to move to the appropriate place and form microtubules. Without microtubules, the cell cannot continue with division, eventually leading to cell death. If a cell does manage to divide, the uniform field can cause genetic material to be unevenly distributed between daughter cells, again resulting in cell death. Imagine one batch of cement mix only gets a few drops of water and the other gets many gallons- neither batch will form a viable product.
When cells are further along in the division process they take on an hourglass shape. For these hourglass shaped cells, the electric fields bend and create a non-uniform electric field. The hourglass shape causes there to be greater field density near the central, pinched region of the dividing cell. This causes molecules to migrate to this location, leading to structural damage of the cell.
Both mechanisms only act on dividing cells, meaning that the treatment does not cause damage to healthy tissue. Optune uses alternating electric fields that frequently switch between horizontal and vertical orientation, forming a crisscross pattern, to affect as many cancerous cells as possible. This supplemental treatment has demonstrated an 8% higher five-year survival rate for glioblastoma patients.
Future research may continue to unlock important, multi-faceted benefits of employing electric fields in clinical cancer therapeutics. Novocure published that alternating electric fields can desirably delay damage repair of cancerous cell DNA following radiation treatment. A team from Stanford published in December of 2018 that electric fields increase the membrane permeability of glioblastoma cells, making it easier for outside molecules to enter the cancer cells. This could mean that electric fields make cancer cells more susceptible to chemotherapy.
Another team from the University of California demonstrated with rats that electric fields can make stem cells migrate more successfully to a specific part of the body, in a process called galvanotaxis. The primary motivation to use stem cells as drug delivery vehicles in cancer therapeutics comes from the fact that stem cells have certain receptors that incline them to migrate toward cancerous cells. However, there is room for improvement with regard to the proportion of therapeutic stem cells that reach the diseased region of the body due to chemotaxis alone. Applying galvanotaxis to supplement the inherent chemotactic ability of stem cells could help therapies overcome this barrier. A key distinction is that unlike the alternating electric fields used by Optune, electric fields used to guide stem cells are unidirectional.
As research continues, we are left to wonder: could electric fields slow tumor growth, enhance chemotherapy, enhance radiation therapy, and guide therapeutic stem cells, ultimately leading to increased survival? One thing is certain. If they do, we will never look at that balloon on a wall the same again.
Images created with BioRender
Works Discussed:
Chang, E., Patel, C. B., Pohling, C., Young, C., Song, J., Flores, T. A., . . . Gambhir, S. S. (2018). Tumor treating fields increases membrane permeability in glioblastoma cells. Cell Death Discovery, 4(1). doi:10.1038/s41420-018-0130-x
Feng, J. F., Liu, J., Zhang, L., Jiang, J. Y., Russell, M., Lyeth, B. G., … Zhao, M. (2017). Electrical Guidance of Human Stem Cells in the Rat Brain. Stem cell reports, 9(1), 177–189. doi:10.1016/j.stemcr.2017.05.035
Giladi, M., Munster, M., Schneiderman, R., Voloshin, T., Porat, Y., Bomzon, Z., . . . Palti, Y. (2017). Tumor Treating Fields (TTFields) Delay DNA Damage Repair Following Radiation Treatment of Glioma Cells: Implications for Irradiation Through TTFields Transducer Arrays. International Journal of Radiation Oncology*Biology*Physics,99(2). doi:10.1016/j.ijrobp.2017.06.088
How Optune Works. (n.d.). Retrieved from- https://www.optune.com/discover-optune/how-optune-works
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