City of Hope's cancer-killing pill works like a snowstorm shutting down an airport

Researchers from City of Hope have pinned down the mechanism behind an oral chemotherapy that is already being tested in humans, adding weight to the preclinical package of data underpinning the drug's potential in a range of solid tumors. 

In a study published Aug. 1 in Cell Chemical Biology, the researchers showed how City of Hope's small molecule AOH1996 targets a cancerous version of the protein proliferating cell nuclear antigen, or PCNA. The therapy was also able to kill cancer cells from more than 70 different solid tumor cell lines, building on pre-investigational new drug-enabling studies on animal models that showed it could eliminate brain, breast, cervical, lung, skin and ovarian cancer cells.

In a press release about the development, senior author scientist Linda Malkas, Ph.D.—whose lab at City of Hope developed the drug and licensed it to RLL, a biotech startup she co-founded—likened AOH1996’s mechanism of action to a snowstorm disrupting air traffic.

“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 us to design a drug that targeted only [the mutated form],” she said. “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.”

The new study showed that AOH1996 kills cancer cells by disrupting the cell reproductive cycle, specifically inhibiting transcription-replication conflicts—a phenomenon that occurs when the cell machinery responsible for genome duplication and gene expression literally run into each other on the spot in the genome. This leads to DNA replication stress, genomic instability and, ultimately, can give rise to cancer.

By targeting mutated PCNA with AOH1996, the researchers kept cells with damaged DNA from dividing while leaving normal cells intact, as shown by studies of the drug’s effects on healthy stem cells.

“We discovered that PCNA is one of the potential causes of increased nucleic acid replication errors in cancer cells,” lead author Long Gu, Ph.D., a researcher at City of Hope, said in the press release. “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.”

AOH1996 is currently being studied alone in a phase 1 clinical trial at City of Hope but some experiments in the current study suggest it made cancer cells more susceptible to chemotherapy agents that work by inducing DNA or chromosome damage, like the drug cisplatin. That means the therapy could be a potential candidate for combination regimens.