Cancer treatment today often includes a painful experience for the patient. Chemotherapy is known to contain powerful substances that kill rapidly dividing cells, even healthy ones. Scientists at Johns Hopkins Medicine and the University of Oxford recently published their results with a new technique they’ve been working on that is capable of killing breast cancer cells while keeping healthy cells safe. One common cause of cancer is a mutation within the genetic coding of a cell that causes it to multiply without anything to suppress it. This unrestricted division of the cell can lead to them becoming cancerous.
While studying lab-grown breast cancer cells, one of the lead researchers, Dr. Holland, noticed a trend amongst them. The cancer cells were dependent on centrioles, which played a crucial role in their survival and multiplication. Centrioles are cylindrical organelles that form necessary spindles in mitosis, a process in which cells divide. They are the core of centrosomes that provide structure for cells and assist in separating DNA during cell division. Although other cells were able to divide without centrioles, these breast cancer cells were not able to. With deeper research, they found that there was a section of the cancer cells that had multiplied a strange amount of times. One specific protein, TRIM37, was being produced excessively by genes in that area. This protein controls centrosomes and when there are high levels of the protein, it results in defective centrosomes instead. These flaws lead to consequences later during cell division and this instability in cell division typically contributes to the development of cancer.
In order to impede the division of cells with an excessive amount of TRIM37, researchers utilized a drug that targeted PLK4 genes. The PLK4 inhibitor specifically hinders the proteins that form centrioles. Unfortunately, they found that adding this drug to their lab-grown breast cancer cells with normal levels of TRIM37 does not impact their cell division even without centrioles. However, for the cells with overexpressed TRIM37, they were unable to divide and died or did not grow anymore. Holland devised a plan to identify cells that contained high levels of TRIM37 and allow the PLK4 inhibitor to kill the breast cancer cells without harming the healthy cells.
They came across precisely why the cancer cells with regular levels of TRIM37 were unaffected by the PLK4 drug. Diagram D shows the effects of the PLK4 inhibitor on a cancer cell with regular levels of TRIM37 compared to a cancer cell with an excessive amount of it. There is a substance called the pericentriolar material (PCM) around the centrioles that performs the same function as centrosomes. In the first path, it states that the “PCM foci promote MT nucleation” which means that the pericentriolar material substitutes for the depleted centrosomes in order for cell division. On the other hand, the cells overexpressing TRIM37 eventually died. The high levels of TRIM37 deteriorates the pericentriolar material and the PLK4 drug stops the production of centrosomes. Without these two, there is no way for the cell division to occur.
This research from Johns Hopkins Medicine and the University of Oxford is a breakthrough in the world of cancer. 9% of breast cancers are caused by the over-expression of TRIM37 and being able to kill these cancer cells while leaving the healthy ones unaffected is a huge step towards finding the best way to treat cancer. Holland and the team are now working on using similar drugs to the PLK4 inhibitor because it is not stable and safe enough to use for patients. In addition, they are testing this inhibitor on other cancer cells to see if they are sensitive as well. Dr. Chapman, another researcher on the team, stated, “We’ve found a previously unknown genetic vulnerability in breast cancer, and discovered a means to exploit this vulnerability and selectively kill cancer cells. We hope that in the future, other researchers and pharmaceutical companies can generate new drugs that can target this process, to produce more effective and safer cancer treatments.”
Nature, “Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer”, 9 September 2020, https://www.nature.com/articles/s41586-020-2690-1
Johns Hopkins Medicine. “New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed.” ScienceDaily. ScienceDaily, 9 September 2020. www.sciencedaily.com/releases/2020/09/200909114901.htm
University of Oxford, “Previously unknown ‘genetic vulnerability’ in breast cancer cells target of research.” 10 September 2020 https://www.ox.ac.uk/news/2020-09-10-previously-unknown-genetic-vulnerability-breast-cancer-cells-target-research#
Johns Hopkins Medicine, “Scientists Identify New Way to Target Some Rapidly Dividing Cancer Cells, Leaving Healthy Cells Unharmed”, 9 September 2020 https://www.hopkinsmedicine.org/news/newsroom/news-releases/scientists-identify-new-way-to-target-some-rapidly-dividing-cancer-cells-leaving-healthy-cells-unharmed
Fierce Biotech, “Blocking tumor cell division to stop breast cancer.” 9 September 2020, https://www.fiercebiotech.com/research/blocking-tumor-cell-division-to-stop-breast-cancer
National Human Genome Research Institute, “Centriole”, https://www.genome.gov/genetics-glossary/Centriole
Sciencing, “What Would Happen If a Cell Didn’t Have Ribosomes?”, 16 April 2018, https://sciencing.com/would-happen-cell-didnt-ribosomes-19003.html
Patient Navigator Training Collaborative, https://www.patientnavigatortraining.org/chronic_disease/module3/1_index.htm