Yesterday researchers at City of Hope, one of the largest cancer research and treatment organizations in the United States, released a new study explaining how they took a protein once thought too challenging for targeted therapy, the nuclear antigen of the cell proliferation (PCNA) and developed a targeted chemotherapy that appears to annihilate all solid tumors in preclinical research. As scientists continue to investigate the fundamental mechanisms that make this cancer pill work in animal models, they note that a Phase 1 clinical trial testing the City of Hope-developed therapy in humans is underway. Most targeted therapies focus on a single pathway, which allows the cunning cancer to mutate and eventually become resistant.
However, the anticancer molecule scientists have developed over the past two decades, AOH1996, targets a cancerous variant of PCNA, a protein that in its mutated form is critical in DNA replication and repair of all growing cancers. In fact, PCNA collaborates with proteins such as p53, PARP1, ATM and RPA70, which serve to trigger the repair systems once the DNA has been damaged by radiation, drugs or oxidizing radicals. AOH1996 has been effective in preclinical research in the treatment of cells derived from breast, prostate, brain, ovarian, cervical, skin and lung cancers. The researchers tested AOH1996, a small molecule inhibitor of PCNA, in more than 70 tumor cell lines and several normal control cells.
They found that AOH1996 selectively kills cancer cells by disrupting the normal cell reproductive cycle. It targets a process called transcript replication conflicts, which occur when mechanisms responsible for gene expression and genome duplication collide. The drug prevented cells with damaged DNA from dividing in the G2/M phase and making a copy of the defective DNA in the S phase. As a result, AOH1996 caused programmed cancer cell death (apoptosis), but did not stop the reproductive cycle of healthy stem cells. It also made cancer cells more susceptible to chemicals that cause damage to DNA or chromosomes, such as the chemotherapy drug cisplatin and alkylators.
Dr. Malkas, the senior author of the new study published in Cell Chemical Biology, explained comprehensively: “The PCNA is like a major hub in an airline terminal containing multiple airline gates. The data suggest that PCNA is uniquely altered in cancer cells and this fact allowed us to design a drug targeting only the form of PCNA in cancer cells. Our cancer pill is like a snowstorm shutting down a major airline hub, shutting down all inbound and outbound flights only on planes carrying cancer cells. AOH1996 can suppress tumor growth alone or in combined treatment in cell and animal models without causing toxicity. The investigational chemotherapy is currently in a Phase 1 clinical trial in humans here at the City of Hope.”
“Nobody ever targeted PCNA as a therapeutic because it was considered ‘uncontrollable with molecules’ but clearly City of Hope was able to develop an investigational drug for a challenging protein target. We found 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 for developing more personalized and targeted cancer medicines.”
By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific publications
Gu L et al. Cell Chemical Biology 2023 Aug 1 in press.
Gu L, Hickey RJ et al. Genes (Basel). 2023; 14(7):1346.