PARP Inhibitors Used in ‘One-two Punch’ Strategy to Kill OC Cells in Mouse Models, Study Shows

PARP Inhibitors Used in ‘One-two Punch’ Strategy to Kill OC Cells in Mouse Models, Study Shows

Researchers have developed a two-step approach that harnesses the aging process of cells, allowing breast and ovarian cancers to be effectively targeted and destroyed in cell and mouse preclinical models.

The “one-two punch” strategy consists of first treating cancer cells with PARP inhibitors — an anti-cancer therapy used in ovarian and breast cancer — that causes them to age. Those “old” cells are then selectively destroyed with the use of senolytic agents, or small molecules that kill aging cells.

The study, Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence,” was published in the journal Nature Communications.

Aging can elicit a variety of stresses that push cells into a process called cellular senescence, where they stop growing and dividing. While this response works to limit the replication of old or damaged cells, the build up of senescent cells in the body may cause a variety of age-related diseases, and cancer.

Because senescent cells influence the outcome of a variety of diseases, scientists have actively explored both pro-senescent and anti-senescent therapies.

A team of researchers at University of Montreal Hospital Research Centre (CRCHUM), in Canada, found a way to exploit the process of senescence to wipe out breast and ovarian cancer more effectively.

The researchers, led by Hubert Fleury, a postdoctoral fellow, Francis Rodier, PhD, and Anne-Marie Mes-Masson, PhD, examined cells with epithelial ovarian cancer (EOC), the most common type of this cancer.

They discovered that  EOC cells enter senescence following chemotherapy in combination with PARP inhibitors, a type of targeted therapy used in advanced and recurrent ovarian cancer. Common PARP inhibitors used in the clinic include Lynparza (olaparib; sold by AstraZeneca), Rubraca (rucaparib; by Clovis Oncology), and Zejula (niraparib; by Tesaro).

These therapies block poly (ADP-ribose) polymerases (PARPs), which are enzymes that help repair damage to DNA. The PARP inhibitors prevent cancer cells from repairing their DNA, stopping them from proliferating and causing them to age prematurely.

Taking advantage of this effect, the researchers then targeted the PARP-treated senescent cancer cells. They destroyed them using a senolytic agent, which is a small molecule that selectively induces the death of senescent cells.

“In the case of epithelial ovarian cancer (EOC) — the most common and lethal ovarian cancer — we act in two stages. 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,” Rodier said in a press release.

In lab models of high-grade serous epithelial ovarian cancer (HGSOC), and triple-negative breast cancer (TNBC) derived from patient tumors, scientists confirmed that combining the PARP inhibitor Lynparza with the senolytic agent ABT-263, killed cancer cells more effectively than Lynparza did alone.

Importantly, they validated the effectiveness of their “one-two punch strategy” for slowing the growth of ovarian and breast cancer in xenograft models, which are transplants of patient tumors into mice. The researchers said this combo may help overcome tumor resistance that can emerge during maintenance therapy with PARP inhibitors.

“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,” Mes-Masson said.

The new discovery will be used to propose clinical trials for ovarian and breast cancer. However, Rodier called attention to the fact that the researchers used preclinical mouse models with a deficient 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,” he said.

According to the National Cancer Institute, 22,530 American women will be diagnosed with ovarian cancer in 2019, and 13,980 will die from the disease. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system.