Researchers at City of Hope have developed a new targeted chemotherapy that shows promise against all solid tumor types, in preclinical studies. The new drug candidate, AOH1996, targets proliferating cell nuclear antigen (PCNA) a protein once that to be “undruggable” with early research showing that the targeted chemotherapy appears to eliminate all solid tumors. Based on their clinical work, the City of Hope Researchers have advanced the candidate into a Phase I clinical trial.
Linda Malkas, PhD, a professor in the Department of Molecular Diagnostics and Experimental Therapetics at City of Hope and senior author of the study, published this week in Cell Chemical Biology, has been developing the cancer-killing therapeutic for roughly 20 years which target a cancerous variant of PCNA, which in its mutated form plays a central role in DNA replication and repair of growing solid tumors.
To describe PCNA’s role, Malkas uses the analogy of an airport where the protein sits as a terminal hub with multiple gates attached. “Data suggests 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,” she notes.
To date, the chemotherapeutic has been tested successfully in cell lines from breast, prostate, lung, brain, ovarian, cervical, and skin cancers. In total, AOH1006 has been tested against 70 cancer cell lines and several normal control cells. It has been licensed a biotechnology company RLL, LLC of which Malkas is a co-founder.
The researchers found that AOH1996—named after Anna Olivia Healey, a girl born in 1996 who subsequently died of cancer—selectively kills cancer cells via disruption of the normal cell reproductive cycle. It does this by targeting transcription replication conflicts that happen with mechanisms for gene expression conflict with genome duplication. According to the study the drug candidate “prevented cells with damaged DNA from dividing in G2/M phase and from making a copy of faulty DNA in S phase. As a result, AOH1996 caused cancer cell death (apoptosis), but it did not interrupt the reproductive cycle of healthy stem cells.”
Long Gu, PhD, lead author of the study and an associate research professor in the Department of Molecular Diagnostics and Experimental Therapeutics says: “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 current Phase I trial of AOH1996 at City of Hope will test the maximum dose tolerated by patients of the new pill, as well as test it for preliminary efficacy. The trial, expected to run through 2024, is open to patients with reoccurring solid tumors whose prior treatments have not been effective. Participating patients will take the medication in pill form twice a day.
Malkas and team note that their experiments with the chemotherapeutic candidate made cancer cells more susceptible to chemical agents that cause DNA damage, like the widely used chemotherapy cisplatin, suggesting it could not only be effective as a single agent, but as part of a combination therapeutic regimen as well.
“Since many patients’ cancers become resistant to our standard therapies, we need new therapeutics with new mechanisms of action— or example, non-cross resistant. AOH1996 is just that kind of new therapy,” said Daniel Von Hoff, M., of the Molecular Medicine Division at the Translational Genomics Research Institute (TGen), part of City of Hope, and an advisor on the study.
Malkas adds that other targeted therapies that inhibit the growth and spread of cancer have been widely adopted and hopes that AOH1996 can eventually win regulatory approval as a targeted chemotherapy that could be used in combination with existing therapies to both enhance cancer-killing effects as well as decrease side effects related to lifesaving cancer treatments.
