Research News

Cleveland Clinic cancer biologist Zihua Gong, MD, PhD, has received $2 million renewal grant from the National Institutes of Health (NIH) to determine whether a DNA repair gene called nudt16 can be used as a biomarker for breast cancers that do not respond to PARP inhibitor therapy. Dr. Gong discovered nudt16 while supported by a previous $1.8 million NIH grant to study BRCA1- and BRCA2- associated breast and ovarian cancers. 

Dr. Gong’s ongoing work demonstrates the research process necessary to identify new opportunities to refine cancer treatments. To create more effective drugs, first researchers need to determine why treatments aren’t working and what the processes in the body to target.  

After starting a research lab in Cleveland Clinic’s Department of Cancer Biology in 2016 and receiving $1.8 million dollars from the NIH in 2018, Dr. Gong has identified multiple genes whose mutations helped BRCA-deficient breast cancers get around PARP inhibitor-resistance. 

What are PARP inhibitors? 

PARP inhibitors destroy cancer cells by blocking them from using a protein called PARP to repair harmful lesions in their DNA. Without the ability to fix problems that occur during replication, cancer cells become unstable and self-destruct. Dr. Gong says that PARP inhibitor therapy has revolutionized the way we treat hereditary breast cancer, but there is still room for improvement: the therapy has an overall response rate of 40%. 

All of our cells, including cancer cells, have multiple ways of detecting and repairing DNA damage caused by genetic mutations. This is usually a good thing: the more ways a cell can “spell check” and repair its DNA, the less likely it is to develop a harmful mutation. When it comes to cancer, however, having multiple DNA repair pathways can do more harm than good by combatting treatment. 

Leveraging the DNA repair gene nudt16 to fight BRCA-deficient breast cancers 

While supported by their 2018 NIH grant, Dr. Gong’s team had identified gene mutations that helped BRCA-deficient cancer cells resist PARP inhibitor therapy. Of the four main genes they found, their most promising candidate was a gene nobody had ever looked at before: nudt16. 

Dr. Gong and his team will use their NIH award to unravel the details of how the nudt16 gene muations restore BRCA-mutant breast cancer cells their ability to repair damaged DNA during PARP inhibitor treatment and determine whether the gene can be used as a biomarker to identify and treat PARP inhibitor-resistant patients. The project started in August of 2024.  

“Identifying new pathways and genes involved in treatment resistance means we can develop tools to identify individuals who won’t respond to therapy,” Dr. Gong says. “Treatments developed can take away the cancers’ survival tools.”