Mechanistic Insights: Decoding How TTFields Disrupt Mitosis in Cancer Cells

Tumor Treating Fields, also known as TTFields, are a relatively new cancer treatment modality that uses alternating electric fields to disrupt cancer cell division. Over the past decade, TTFields have shown promise in treating some advanced cancers and are now an approved treatment for certain forms of brain cancer and mesothelioma. This article provides an overview of what TTFields are, how they work, the current research and clinical applications.

What are Tumor Treating Fields?

Tumor Treating Fields, or TTFields, are a non-invasive anti-mitotic treatment that utilizes low-intensity alternating electric fields. These fields disrupt the normal division of cancer cells during mitosis, preventing them from accurately separating chromosomes. The alternating electric fields generate physical forces that pull on charged molecules and ions within dividing cancer cells. This interference disrupts mitotic spindle formation and chromosome separation, blocking the cells from completing mitosis. As a result, cancer cells cannot replicate and tumors cannot grow.

TTFields differ from chemotherapy and radiation in several important ways. Unlike chemotherapy, they selectively target rapidly dividing cancer cells while largely sparing healthy cells. And unlike radiation therapy, they do not directly damage DNA or cause ionizing radiation effects. TTFields operate via purely physical mechanisms to disrupt mitosis in cancer cells. They can be applied continuously for longer periods with minimal side effects compared to chemotherapy or radiation.

How TTFields Work at a Molecular Level

During the process of cell division known as mitosis, proteins called tubulins polymerize to form the mitotic spindle - a structure that segregates copies of the chromosomes to the two daughter cells. Alternating electric fields generated by Tumor Treating Fields cause physical lateral displacement of the charged molecules that make up the spindle.

Specifically, the electric fields pull on the electrically charged nitrate and carbonyl groups within the tubulin molecules. This physical perturbation disrupts the proper assembly of the mitotic spindle fibers. Without a correctly formed spindle, the dividing cancer cell cannot accurately separate its chromosomes between the two daughter cells. As a result, the cancer cell is unable to complete cell division and dies. Healthy cells with lower mitotic indices are relatively unaffected.

Current Clinical Applications

Over the past decade, several large clinical trials have established TTFields as an effective treatment for recurrent glioblastoma and malignant pleural mesothelioma. TTFields are delivered using transducer arrays applied to the shaved scalp in glioblastoma or plaster-like patches applied to the chest wall in mesothelioma. Treatment involves wearing the transducer arrays for over 18 hours per day. Significant survival benefits have been observed compared to best standard of care alone in these difficult-to-treat cancers.

Based on their demonstrated clinical efficacy, TTFields received FDA approval in 2015 for recurrent glioblastoma and in 2021 for unresectable malignant pleural mesothelioma. Ongoing trials are evaluating TTFields as a first-line or neoadjuvant treatment in these cancers as well as in earlier-stage solid tumors. Recent research is also exploring combining TTFields with immunotherapy and targeted drugs to enhance anti-tumor effects. As further clinical evidence accrues, TTFields may expand to treat additional advanced solid cancers in the future.

Novel Mechanisms and Applications

While TTFields were originally conceived as an anti-mitotic treatment, recent research has uncovered additional anti-tumor mechanisms of action. Studies show TTFields can impair DNA repair pathways, disrupt angiogenesis within tumors, and induce immunogenic cancer cell death. These findings broaden the scope of TTFields beyond specifically targeting mitosis. Ongoing preclinical work is exploring synergistic combinations of TTFields with immune checkpoint inhibitors, radiation therapy, and targeted drugs in a variety of solid tumors.

One emerging application is using TTFields to enhance checkpoint blockade immunotherapy. In animal models, TTFields sensitize tumors to PD-1/PD-L1 inhibitors by promoting immunogenic cell death and T-cell infiltration into tumors. TTFields may function as an "in situ vaccine" to boost anti-tumor immune responses when combined with checkpoint therapy. This combination approach holds promise for treating "cold" tumors less responsive to immunotherapy alone. Clinical trials are underway to evaluate TTFields combined with anti-PD-1 drugs.

Finally, TTFields are being explored as a precision medicine tool guided by patient-specific tumor characteristics. Factors like tumor type, growth rate, and molecular profile may determine how responsive individual cancers are to TTField treatment. Ongoing work aims to identify predictive biomarkers that allow customizing TTFields therapy based on a patient’s specific tumor biology. Such personalized approaches could optimize clinical outcomes from this promising non-invasive cancer treatment technology.

Tumor Treating Fields are an approved and effective form of physical tumor treatment that harness low-intensity electric fields to disrupt cancer cell division. Over the last decade, clinical studies have demonstrated significant survival benefits from TTFields therapy in recurrent glioblastoma and mesothelioma. Ongoing research continues to elucidate additional anti-tumor mechanisms of action and explores combining TTFields with other modalities like immunotherapy. Continued clinical trials will help determine how broadly applicable this non-invasive technology can become across cancer types. With further advances, Tumor Treating Fields hold great promise for improving outcomes for many solid tumor patients.

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