Researchers at City of Hope, one of the largest cancer research and treatment organizations in the United States, published a new study explaining how they took a protein once thought to be too challenging for targeted therapy, proliferating cell nuclear antigen (PCNA), and developed a targeted chemotherapy that appears to annihilate all solid tumors in preclinical research. As the scientists continue to investigate the foundational mechanisms that make this cancer-stopping pill work in animal models, they note that there is an ongoing Phase 1 clinical trial testing the City of Hope-developed therapeutic in humans.
Most targeted therapies focus on a single pathway, which enables wily cancer to mutate and eventually become resistant. However, the new cancer-killing pill 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.
PCNA is like a major airline terminal hub containing multiple plane gates. Data suggests PCNA is uniquely altered in cancer cells, and this fact allowed the researchers to design a drug that targeted only the form of PCNA in cancer cells. This cancer-killing pill is like a snowstorm that closes a key airline hub, shutting down all flights in and out only in planes carrying cancer cells. The researcher says that the 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 a Phase 1 clinical trial in humans at City of Hope.
AOH1996 has been effective in preclinical research treating cells derived from breast, prostate, brain, ovarian, cervical, skin and lung cancers and is exclusively licensed by City of Hope to RLL, LLC, a biotechnology company.
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.
The researcher says that no one has ever targeted PCNA as a therapeutic because it was viewed as ‘undruggable,’ but City of Hope was able to develop an investigational medicine for a challenging protein target.
As a next step, the researchers will look to better understand the mechanism of action to further improve the ongoing clinical trial in humans.
News Source: City of Hope
