Targeted Chemotherapy Pill Destroys All Solid Tumors in Early Testing

Researchers at the City of Hope developed a targeted chemotherapy that, in preclinical research, appeared to destroy all solid tumors using proliferating cell nuclear antigen (PCNA), a protein once thought to be too challenging for targeted therapy. Their research was published in Cell Chemical Biology.

Most targeted therapies focus on a single pathway, which enables cancer to mutate and eventually become treatment resistant. This cancer-killing pill, known as AOH1996, targets a cancerous variant of PCNA. PCNA in its mutated form is critical to DNA replication and repair of all expanding tumors, wrote Linda Malkas, PhD, dean of translational science and external affairs and the M.T. & B.A. Ahmadinia Professor in Molecular Oncology at the City of Hope. Dr. Malkas helped develop the therapy and is the senior author of the study.

“PCNA is like a major airline terminal hub containing multiple plane gates. Data suggest PCNA is uniquely altered in cancer cells, and this fact allowed us to design a drug that targeted only the form of PCNA in cancer cells. Our 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,” Dr. Malkas said. “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 investigators tested AOH1996 in more than 70 cancer cell lines and in normal control cells. They observed that AOH1996 is effective at killing cancer cells by disrupting the normal cell reproductive cycle and targeting transcription replication conflicts, which occur when mechanisms that facilitate gene expression and genome duplication collide. The pill prevented damaged cells from dividing in the G2/M phase and subsequently mutating. Essentially, AOH1996 caused cancer cell death without harming healthy cells.

“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, PhD, lead author of the study and an associate research professor in the Department of Molecular and Cellular Biology at the 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.”

The City of Hope is currently running a phase 1 clinical trial in humans for AOH1996.