Working with cell cultures, researchers found that an enzyme they call isocitrate dehydrogenase 1 (IDH1) encourages the proliferation of high-grade serous ovarian cancer cells.
When they blocked the enzyme, either chemically or by silencing its gene, the cancer cells lost their ability to divide and multiply.
Loss of the enzyme’s activity appeared to put the cancer cells into a state of senescence. Cells that enter this dormant state cannot complete their cell cycle.
A recent paper in the journal Molecular Cancer Research gives a detailed account of the study.
“One of the biggest problems of cancer cells,” says senior study author Katherine M. Aird Ph.D., assistant professor of cellular and molecular physiology at Penn State College of Medicine in Hershey, PA, “is they can grow forever without stimulus.”
“By inducing senescence, the cells can no longer divide and grow,” she adds.
Need for new types of treatment
Cancer is a disease that develops when abnormal cells grow out of control and form a mass, or tumor. When the cells that grow out of control are in the ovaries, they give rise to ovarian cancer.
Around 1 in 78 women will develop ovarian cancer during their lifetime. The chances of surviving more than 5 years after diagnosis are more than 90% when diagnosis occurs in the very early stages.
However, because the symptoms are vague, and there are no tests for early detection, early diagnosis only occurs in around 20% of cases. Most people with ovarian cancer do not find out that they have the disease until cancer has started to spread.
The new study concerns high-grade serous ovarian cancer, which is the most common type of ovarian cancer.
Around 70% of those with high-grade serous ovarian cancer will experience relapse because the cancer has a tendency to develop resistance to chemotherapy. There is an urgent need for new approaches to treating this disease.
As most women with high-grade serous ovarian cancer do not receive a diagnosis until the disease has started to spread, it is difficult to pinpoint its origins.
Traditionally, doctors believed that the cancer started on the tissue that lines the surface of the ovaries. More recently, however, opinion has shifted to suspect the fallopian tube as the origin.
Targeting the citric acid cycle
For their study, Aird and her colleagues compared how healthy and cancerous fallopian tube cells used sugar. The researchers did this by measuring the byproducts of cell metabolism using mass spectrometry.
From the spectrometry results, the team deduced that the cancer cells favored using sugar in the citric acid cycle. In contrast, the healthy cells favored converting sugar to lactate, using aerobic glycolysis, which is more common.
Many cancer treatments target glycolysis because cancer cells use this route to meet their high demand for energy.
However, targeting glycolysis “may not be the best approach,” says lead study author Erika S. Dahl, a doctoral student at Penn State College of Medicine.
She explains that because healthy cells use this route for converting sugar into energy, targeting glycolysis can also damage healthy tissue.
IDH1 plays a central role in the citric acid cycle. The team found that blocking the enzyme stopped cell division in its tracks.
Treatment could target later stages of cancer
It appears that blocking the enzyme works not only in cells in the primary tumor site, but that it can also arrest the cell cycle of cancer cells that have spread to other parts of the body.
This finding is in line with evidence from other studies that shows progression-free survival tends to be longer when levels of the enzyme are low.
As most women who develop ovarian cancer do not receive a diagnosis before their cancer has spread, it is essential that new treatments can target later stages of the disease.
The form of IDH1 that the researchers identified in high-grade serous cancer cells is the wildtype, or nonmutant, form.
Aird explains that the Food and Drug Administration (FDA) have already approved a drug that targets the mutant form of IDH1.
“One of our long term goals is to try and repurpose this already approved drug as a treatment for this form of ovarian cancer.”
Katherine M. Aird Ph.D.