Researchers at Tel Aviv University have successfully used RNA nanodrugs to target and silence a gene that encodes for a protein that causes ovarian cancer to metastasize.
This breakthrough achieved by a TAU research team led by Prof. Dan Peer of the Shmunis School of Biomedicine and Cancer Research provides hope for a possible treatment for aggressive and metastatic cancers resistant to chemotherapy and immunotherapy.
Peer spoke recently to The Times of Israel about the research, which was published in the peer-reviewed Science Advances journal in April, and why he is excited about what it could eventually mean for patients for whom all other therapeutic options have been exhausted.
“In cases like metastatic ovarian cancer, the arsenal for the oncologist is gone. It gets to a point when the tumor is highly metastasized and there is nothing more to offer to the patient and their families,” Peer said.
Globally, ovarian cancer affects 1 in 78 females and is the fifth deadliest malignancy in women. However, the prevalence of the BRCA1 and BRCA2 mutations among Ashkenazi Jewish women makes it more likely they will develop the disease. A woman with the BRCA1 mutation has an estimated 39-46 percent risk of developing ovarian cancer by age 70.
There is no reliable screening method for ovarian cancer and symptoms often go unnoticed, usually leading to diagnosis at advanced stages of the disease, when it has already spread to other organs. When it comes to survival rates, 93% of women whose ovarian cancer is diagnosed at an early stage can expect to live at least five years, but only 31% of those diagnosed at an advanced stage can expect to live for that long.
Peer and his team decided to tackle a very basic mechanism in cancerous tumors — uncontrolled cell division.
“We decided to block this division process by silencing a special gene that encodes for a special protein that is responsible for those changes in the cell division,” he said.
The specific protein is CKAP5 (cytoskeleton-associated protein), which is produced by a genetically unstable mutation resistant to both chemotherapy and immunotherapy in the tissues of ovarian cancer. The scientists targeted the metastasized ovarian cancer cells with lipid nanoparticles containing RNA for silencing CKAP5. This caused the cells to collapse and achieved an 80% survival rate in animal models (mice).
The effect of the CKAP5 silencing was evident by the arrest of cell division in ovarian cancer cells, while normal control cells were not affected.
“This shows that cytotoxicity is specific only for cells with high chromosomal abnormalities — a hallmark of ovarian cancer cells — absent in normal noncancerous cells, highlighting CKAP5 as a unique and attractive target,” said Dr. Rachel Michaelson-Cohen, an obstetrician-gynecologist and the director of the prenatal genetics unit at Shaare Zedek Medical Center, The Hebrew University of Jerusalem.
Michaelson-Cohen, who reviewed the TAU study at The Times of Israel’s request, said she would like to see this approach tested on late-stage ovarian cancer metastasis, and also other cancers that metastasize similarly to the intraperitoneal cavity, such as pancreatic, colorectal and liver cancer.
Peer confirmed that he intends to test the silencing of CKAP5 in a variety of other cancers.
“[CKAP5] is not only in ovarian cancer. We used ovarian as a proof of concept, but in a week from now, we have another paper coming on multiple myeloma with the same target.” Peer said.
He estimates that this technology will be offered in human trials two to three years from now.
“There is a California company that picked up these technologies and is working with us. They are mostly going after a hematological blood cancer called acute myeloid leukemia (AML), but ovarian cancer is number two,” Peer said.
He is personally invested in trying to cure ovarian cancer, which killed his mother-in-law at a young age.
“We have been committed to finding a solution to this since 2005,” he said.
The ultimate goal is to not only silence the genes that cause ovarian and other cancers to metastasize, but to edit them completely from the genome. This would mean the difference between regular ongoing treatments and the ability to stop the disease in its tracks with just one or two doses of an RNA nanodrug.
“There is some evidence right now that this can be done clinically in a rare genetic liver disease. They’re injecting a single dose. It’s been three years already and the data is very good,” Peer said.
“But that is a rare genetic disease, which is caused by a single gene. There’s just one gene to take out. Cancer is a little bit more complex. We can take out two, or three genes at the same time. But let’s start with one,” he said.