New protein target for fatal ovarian cancer

A new study shows that targeting a specific protein in fast-spreading high-grade serous carcinoma (HGSC) could help contain these cancers. HGSC is the most common and deadliest form of epithelial ovarian cancer, which is itself the most lethal cancer of the female reproductive system. When the HGSC spreads outside the ovaries, into the peritoneal cavity, it forms loose balls called spheroids, which may be different from the adherent cells of the primary tumor.

The study is published in the latest issue of the journal Molecular Cancer Research.

Illustration of a cancer cell. Image credit: Jovan Vitanovski / Shutterstock

70% of HGSC patients relapse despite treatment, becoming resistant to chemotherapy, making this new discovery a real breakthrough in the treatment of this tumor.

All life at the cell and organ level is dependent on thousands of vital processes that provide and degrade a range of chemicals necessary for the proper functioning of cells and tissues. Together, these closely interdependent processes make up the body's metabolism.

However, as researcher Erika Dahl explains, "A hallmark of cancer cells is that their metabolic processes are often different from those of normal healthy cells." This is what is called metabolic reprogramming . The author of the study, Katherine Aird, said, "Cancer cells can grow forever without stimulus."

The good news about the newly discovered protein is that it can be inhibited, thus inactivating cellular processes within ovarian cancer cells from a constitutively proliferating cell cycle to a cycle that leads to senescence or sleep. Researchers at the Penn State College of Medicine have identified the key role of the protein in cell culture experiments.

The current study aimed to reduce differences in ovarian cancer cell metabolism by comparing them to normal fallopian tube cells.

The pathway used to achieve this was quantitative spectrometry, which allowed badysis of metabolites produced by different cell pathways in both tissue types. Among the differences, it was revealed that cancer cells much more often used glucose, a form of sugar, via the key energy cycle called the citric acid cycle, compared with the more common use of A pathway requiring oxygen called aerobic glycolysis. This explains the presence of high activity of citric acid in all serous ovarian cancer cells of high grade.

This means that many treatments that inhibit the breakdown of glucose (glycolysis) to destroy cancer cells can be quite inefficient. Dahl commented that this could often lead to the production of harmful toxins for normal healthy tissue.

The team of the present study rather investigated the effects of wild-type inhibition or the normal form of an enzyme, isocitrate dehydrogenase 1 (HDI 1), which plays a essential role in the cycle of citric acid. They selected this protein because it was the only one in this pathway to express at higher levels in adherent tumor cells and spheroids. The increased activity of this enzyme has serious implications for progression-free survival, which is an important outcome for badessing the effectiveness of any cancer treatment.

Mutants of this protein are common in other tumors, but the wild type form is usually present in HGSC cells. The researchers hypothesized that the presence of this enzyme is an important benefit for these cells and that its inhibition is a key step in the induction of senescence.

The researchers found that suppressing the work of this protein completely disrupted cell division by suppressing the activity of several other genes, thereby inhibiting vital metabolic pathways. The adherent cells of the primary tumor and the spheroidal cells of the secondary HGSC become senescent when the wild-type enzyme IDH 1 is inhibited. So, this could be a great way to treat HGSC at all stages. This is an important consideration because ovarian cancers are rarely diagnosed at an early stage.

Although there are already FDA (US Food and Drug Administration) -approved drugs against one of the mutant forms of this enzyme, the team is asking for it. would also act against the wild form. They found that was the case, and it's now part of their ongoing research agenda.

"One of our long-term goals is to try to reuse this drug already approved as a treatment for this form of ovarian cancer." In addition to the need to adapt the existing drugs to the enzyme to fight this type of cancer, the researchers wish to: examine in more detail the differences in metabolic functioning of normal cells and HGSC cells. Another goal is to examine the effectiveness of the combination of IDH 1 inhibitors with other treatments.