Eliminating Ovarian Cancer with a ‘One-Two Punch’

Researchers from the University of Montreal Hospital Research Centre (CRCHUM) have developed a two-step combination therapy to destroy cancer cells. Their study, published today in Nature Communications, shows the superior therapeutic effectiveness of the ‘one-two punch’ on cells of ovarian cancer patients by manipulating their state of cellular aging.

With time, our cells age and enter a phase called cellular senescence. These senescent cells stop proliferating, build up in the body, and cause the development of diseases such as cancer. In recent years, the scientific community has tried to heal these aging-related pathologies by targeting and destroying senescent cells.

“In the case of epithelial ovarian cancer (EOC)—the most common and lethal ovarian cancer—we act in two stages,” says senior author Francies Rodier of CRCHUM. “First, we force the cancer cells to age prematurely—i.e., we force them into senescence. This is the first therapeutic punch. We throw our second punch using senolysis, destroying and eliminating them. This strategy requires excellent coordination of the two steps.”

The researchers discovered that EOC cells enter senescence following chemotherapy in combination with PARP inhibitors. PARPs are enzymes that help repair damage to DNA. By blocking PARPs, PARP inhibitors prevent cancer cells from repairing their DNA, stop them from proliferating, and cause them to age prematurely.

“Thanks to our ‘one-two punch’ approach, we have managed to destroy senescent EOC cells in preclinical ovarian cancer models. Our approach could improve the effectiveness of chemotherapy in combination with PARP inhibitors and counteract the systematic resistance that develops with this treatment,” says co-corresponding author Mes-Masson, also of CRCHUM.

Although the results of this study will be used to propose clinical trials for ovarian and triple-negative breast cancer, Rodier says that it is important to remember that they used preclinical models in which there was no immune system. “Given the importance of the immune response in humans, we need to continue evaluating our strategy in a context closer to biological reality.”