USA— Researchers at the City of Hope, one of the largest cancer research and treatment organizations in the U.S., have published a new study on their experimental targeted chemotherapy pill that appears to destroy all solid tumors without affecting healthy cells.
The researchers describe how they took a protein once thought to be too challenging for targeted therapy, the proliferating cell nuclear antigen (PCNA), and developed targeted chemotherapy that appears to annihilate all solid tumors in preclinical research.
Scientists at the center are continuing to investigate the foundational mechanisms that make this cancer-stopping pill work in animal models.
The City of Hope in an official statement notes that there is an ongoing Phase 1 clinical trial testing the City of Hope-developed therapeutic in humans.
The chemotherapy pill has been developing over the past two decades and officially named the AOH1996, targets a cancerous variant of PCNA, a protein that in its mutated form is critical in DNA replication and repair of all expanding tumors.
Dr. Linda Malkas, Ph.D., professor in City of Hope’s Department of Molecular Diagnostics and Experimental Therapeutics, “Most targeted therapies focus on a single pathway, which enables wily cancer to mutate and eventually become resistant.”
Dr. Malkas described PCNA as like a major airline terminal hub containing multiple plane gates and the data suggests PCNA was uniquely altered in cancer cells, and this fact allowed the team to design a drug that targeted only the form of PCNA in cancer cells.
“Results have been promising. AOH1996 can suppress tumor growth as a monotherapy or combination treatment in cell and animal models without resulting in toxicity. The investigational chemotherapeutic is currently in Phase 1 clinical trial in humans at City of Hope,” Dr. Malkas added.
A twenty-year-old journey to honor a little girl’s life.
Scientists have developed what is being seen as a groundbreaking “cancer-killing pill” which was named in honor of a nine-year-old girl who died of the deadly disease.
The therapy is called AOH1996 and uses the initials and the year of birth of Indiana’s Anna Olivia Healey.
AOH1996 has shown “promising results” and can suppress tumor growth “as a monotherapy or combination treatment in cell and animal models without resulting in toxicity”.
“We were too late to help Anna, but we could help others like her. I always say when you see me, there’s a small nine-year-old girl sitting on my right shoulder. She’s, my touchstone,” Dr. Malkas quipped.
Anna was born in 1996 in Indianapolis, US, and was suffering from neuroblastoma, a childhood cancer, and battled the disease for five years.
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 something called 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 in the G2/M phase and from making a copy of faulty DNA in the S phase.
As a result, AOH1996 caused cancer cell death (apoptosis), but it did not interrupt the reproductive cycle of healthy stem cells.
“No one has ever targeted PCNA as a therapeutic because it was viewed as ‘undruggable,’ but clearly the City of Hope was able to develop an investigational medicine for a challenging protein target,” said Dr. 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.
Dr. Gu added that they discovered that PCNA had 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,” Dr. Gu emphasized.
City of Hope’s remarkable work in developing 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.
Moreover, hinting that AOH1996 could become a useful tool in combination therapies as well as for the development of new chemotherapeutics.
“City of Hope has evolved into a world leader in cancer research. They also have the infrastructure to drive translational drug discovery from the laboratory into the clinic for patients in need,” said Dr. Daniel Von Hoff, M.D., study co-author and a distinguished professor at Translational Genomics Research Institute, part of the City of Hope.
City of Hope’s groundbreaking translational 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.
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