Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other malignancy of the female reproductive system. A woman’s risk of getting ovarian cancer during her lifetime is about one in 78 and her lifetime chance of dying from it about one in 108. It is usually discovered when it has spread and difficult to overcome.
But in a study conducted at Tel Aviv University (TAU), the protein CKAP5 (cytoskeleton-associated protein) was used for the first time as a therapeutic target for RNA-based nanodrugs. These drugs deliver ultrafine nanoparticles of treatment – matter that is between 1 and 100 nanometres in diameter. One nanometer is one billionth of a meter.After identifying a genetically unstable mutation resistant to both chemotherapy and immunotherapy in the tissues of ovarian cancer, the researchers targeted these cells with lipid nanoparticles containing RNA for silencing CKAP5, causing the cells to collapse and achieving an 80% survival rate in animal models.
How was this medical breakthrough accomplished?
The breakthrough was achieved by a TAU research team led by Prof. Dan Peer of the Shmunis School of Biomedicine and Cancer Research, a global pioneer in the development of RNA-based drugs, who is director of the Precision Nanomedicine Lab and TAU’s vice president for researcher and development.
His co-author was Dr. Sushmita Chatterjee, a post-doctoral student from India in collaboration with Prof. David Sprinzak of the Wise Faculty of Life Sciences and Prof. Ronen Zaidel-Bar of the Sackler Faculty of Medicine.The study was published in /Science Advances/ under the title “Therapeutic gene silencing of CKAP5 leads to lethality in genetically unstable cancer cells.”The first-line treatment of ovarian cancer includes maximal surgical removal of the tumor, followed by neoadjuvant chemotherapy with platinum/taxane drugs, they wrote. Although 60 to 80% of patients initially respond to chemotherapy, 80% to 85% will develop chemo-resistance, so there is a constant search for new therapeutic targets in ovarian cancer.“The protein CKAP5 has never been studied with relation to the fight against cancer, simply because there was no known way to silence it,” explained Chatterjee. “The lipid nanoparticles developed by Prof. Peer enabled us for the first time to silence this protein through targeted delivery of an RNA drug. We proved that CKAP5, a protein responsible for the cell’s stability, can be silenced, and that this procedure collapses and destroys the entire cancer cell.”At the second stage of the study the researchers tested the new CKAP5-silencing RNA drug on 20 types of cancer. Some malignant cells proved more sensitive than others to this procedure. Cancers displaying high genetic instability, which are usually highly resistant to chemotherapy, were found to be especially sensitive to the silencing of CKAP5.“All cancer cells are genetically unstable,” Chatterjee continued.
“Otherwise, they would be healthy, not cancerous. However, there are different levels of genetic instability. We found that cancer cells that are more unstable are also more affected by damage to CKAP5. Our drug pushed them to their limit and essentially destroyed their structure.
“Our idea was to turn the trait of genetic instability into a threat for these cells by using RNA to silence the flawed protein. We showed for the first time that CKAP5 can be used to kill cancer cells and then observed the biological mechanism that causes the cancer cells to collapse in the protein’s absence.” Equipped with these insights, the researchers tested the new drug in an animal model for ovarian cancer and achieved a survival rate of 80%.“We chose ovarian cancer, because it’s a good target,” noted Peer. “While highly resistant to both chemotherapy and immunotherapy, this type of cancer is very sensitive to the silencing of CKAP5. The CKAP5 protein is a new target in the fight against cancer.“Targeting cell division is not new, but using RNA to target proteins that make up the cell’s cytoskeleton is a new approach and a new target that must be further investigated.“As researchers, we are involved in something like a game of dominos – we always look for the one piece in the cancer’s structure that is so important that if we pull it out, the entire cell will collapse. CKAP5 is such a domino piece, and we are already working on more applications, this time in blood cancers.”