The researchers tested AOH1996, a small molecule PCNA inhibitor, in more than 70 cancer cell lines and several normal control cells. They found that AOH1996 selectively kills cancer cells by disrupting the normal cell reproductive cycle. It targets transcription replication conflicts, which occur when mechanisms responsible for gene expression and genome duplication collide. The investigational therapy prevented cells with damaged DNA from dividing and from making a copy of faulty DNA. As a result, AOH1996 caused cancer cell death, but it did not interrupt the reproductive cycle of healthy stem cells.
Therapeutic
“No one has ever targeted PCNA as a therapeutic because it was viewed as ‘undruggable,’ but clearly City of Hope was able to develop an investigational medicine for a challenging protein target,” said Long Gu, Ph.D., lead author of the study and an associate research professor in the Department of Molecular Diagnostics and Experimental Therapeutics at Beckman Research Institute of City of Hope. “We discovered that PCNA is one of the potential causes of increased nucleic acid replication errors in cancer cells. Now that we know the problem area and can inhibit it, we will dig deeper to understand the process to develop more personalized, targeted cancer medicines.”
Interestingly, experiments showed that the investigational pill made cancer cells more susceptible to chemical agents that cause DNA or chromosome damage, such as the chemotherapy drug cisplatin, hinting that AOH1996 could become a useful tool in combination therapies as well as for the development of new chemotherapeutics. It is hoped the breakthrough could lead to more personalised, targeted medicines for cancer in the future.
City of Hope’s groundbreaking research history includes developing the technology underlying synthetic human insulin, a breakthrough in diabetes management, and monoclonal antibodies, which are integral to widely used, lifesaving cancer drugs, such as Trastuzumab, Rituximab and Cetuximab.
As a next step, the researchers will look to better understand the mechanism of action to further improve the ongoing clinical trial in humans.
