shadow
Image Credit: "National Ovarian Cancer Coalition" by MTSOfan is licensed under CC BY-NC-SA 2.0

Ovarian cancer is a deadly form of cancer many women experience. About 13,770 women die from ovarian cancer in 2021, which ranks it fifth in cancer deaths among women. Doctors are still trying to figure out how to control this intractable tumor type. Late-stage ovarian cancer is the deadliest form of ovarian cancer. For many other cancer types, using an approach known as personalized medicine can improve the effectiveness of cancer treatment. This approach is based on the particular characteristics of a person’s tumor, namely which mutations are present.

In a personalized treatment, doctors first identify the genetic mutation that contributed to cancer cell growth in a particular patient. Once the tumor is characterized, doctors will use a therapy known to be effective against tumors with that particular mutation. This strategy has allowed doctors to kill other tumors successfully. However, it is not easy to cure late-stage ovarian cancer because few ovarian cancer mutations have been matched to effective therapies.

Ovarian cancers have mutations that make their DNA repair and replication processes vulnerable and weak — the cells cannot fix themselves if things go wrong. Because ovarian cancer cells lack robust repair functions, this can be exploited to kill the tumor in a process called synthetic lethality. It tricks cells into thinking it’s time to self-destruct.

For targeting ovarian cancer, this synthetic lethality is established by using inhibitors targeting a gene called PARP1/2, which codes for an enzyme called PARP. PARP is involved in repairing broken or damaged DNA. PARP inhibitors block this enzyme in cells, which may prevent cancer cells from fixing their damaged DNA, causing them to die. Inhibitors targeting PARP may be able to treat women with high-grade ovarian cancer.

Another enzyme, called PARG, reverses the action of the PARP enzyme. These enzymes work by attaching to damaged sections of DNA and changing the structure of molecules that control the DNA damage machinery. Successful DNA repair requires that both PARP and PARG enzymes are functional, to keep each other in check. So, PARG is yet another useful target for personalized ovarian cancer treatment.

The famous BRCA 1 and BRCA2 genes that protect women from getting breast cancer are involved in this PARP/PARG interplay as well. Certain mutations in BRCA1 or BRCA2 can make cells sensitive to PARP interference. This sensitivity leads to a synthetic lethality condition where the combined effects of BRCA mutations and PARP inhibition kills ovarian cancer cells.

In a recent study, a group of scientists from the UK evaluated whether a combination of PARG inhibitors and a second drug that interferes with DNA replication will be “synthetically lethal” to ovarian cancers. The scientists wanted to know if high-grade ovarian cancers are sensitive to the inactivation of PARG and if so, the cause of the sensitivity. They also wanted to know if inactivating the PARG enzyme is effective in treating ovarian cancer where PARP inactivation alone doesn’t work.

By culturing several types of cancer cells in the lab and treating them with different combinations of drugs, the researchers demonstrated that the inhibitors of PARP are successful in killing BRCA-mutant ovarian cancer cells. However, only 15% to 20% of ovarian cancers contain these mutations. The remaining types were perfect test cases to see if adding a PARG inhibitor would help. Indeed, some of the ovarian cancer cell lines were sensitive to a PARG inhibitor.

PARG inhibition is deadly to tumor cells because it prevents DNA replication from occurring. Cells are either sensitive to PARP inhibitors or PARG inhibitors, but not both, since the two proteins are involved in the same process. Because of this, the study demonstrates that PARG inhibitors have the potential to complement PARP inhibitors in the treatment of ovarian cancer.

But why do these PARG inhibitor-sensitive cells have these replication weaknesses? The mechanism remains unclear but answering this question will help predict the state of the developing cancer. The scientists conclude that an important next step will be a detailed analysis of DNA replication in these particular ovarian cancer cells.

Sensitive cells can resist brief periods of PARG inhibition, despite a DNA replication weakness. However, extended exposure to PARG inhibitors slows the cells’ development. PARG inhibitors suitable for clinical evaluation are not yet available. The observations in the study can help in the design of human trials testing clinical candidates. Efforts to test PARG inhibitors should focus on tumors considered unlikely to be responsive to PARP inhibitors.

Study Information

Original study: DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors

Study published on: 18 March 2019

Study author(s): Nisha Pillay, Anthony Tighe, Louisa Nelson, Samantha Littler, Camilla Coulson-Gilmer, Nourdine Bah, Anya Golder, Bjorn Bakker, Diana C.J. Spierings, Dominic I. James, Kate M. Smith, Allan M. Jordan, Robert D. Morgan, Donald J. Ogilvie, Floris Foijer, Dean A. Jackson, Stephen S. Taylor

The study was done at: University of Manchester (UK), University of Groningen (Netherlands)

The study was funded by: Cancer Research UK, Wellcome Trust PhD studentship to one author

Raw data availability: Nopt provided

Featured image credit: "National Ovarian Cancer Coalition" by MTSOfan is licensed under CC BY-NC-SA 2.0