Cancer Drug Selectively Kills Tumor Cells in Preclinical Study

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In a preclinical study, City of Hope researchers have shown how a new cancer drug was able to kill cells from all tested solid tumors while leaving healthy cells unaffected. The drug, which targets a protein previously thought “undruggable”, is now being tested in a small number of patients in a Phase 1 clinical trial.

The research is published in Cell Chemical Biology.

Professor Linda Malkas, a researcher in City of Hope’s Department of Molecular Diagnostics and Experimental Therapeutics, has been working on the development of the cancer-killing drug AOH1996 over the past two decades. Named after Anna Olivia Healey, a young girl born in 1996 who sadly died at just 9 years of age from neuroblastoma, AOH1996 targets a cancer-causing variant of a protein called proliferating cell nuclear antigen (PCNA).

PCNA is involved in DNA synthesis and repair, but a cancer-associated form of PCNA can drive cancer cell growth, making it an attractive target for anti-cancer therapies.

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“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 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,” said Malkas, senior author of the new study, which characterized the molecular action of AOH1996.

The researchers tested AOH1996 in over 70 cancer cell lines and several normal control cells, discovering that it selectively kills cancer cells by disrupting their normal reproductive cell cycle. AOH1996 was effective in lab-grown cells derived from several different cancer types including breast, prostate, brain, ovarian and lung cancers.

The findings revealed that AOH1996 targets transcription–replication conflicts, which occur when mechanisms responsible for gene expression (which produces proteins) and genome duplication (part of the cell cycle required for cell division) collide.

The drug prevented cells with damaged DNA from dividing and from making copies of the faulty DNA, therefore leading to cell death (apoptosis) in the cancer cells, but not interrupting the reproductive cycle of healthy stem 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 Dr. Long Gu, lead author of the study and an associate professor at 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.”

Further experiments by the team also showed that the investigational drug increased the sensitivity of lab-grown cancer cells to cisplatin, a widely used chemotherapy drug. Chemical agents like cisplatin damage DNA or chromosomes, hinting that AOH1996 could prove useful in combination with other therapies as well as for the development of new chemotherapeutics.

Experiments in mice bearing implanted tumors (xenografts) derived from either neuroblastoma, breast cancer or small cell lung cancer cells also showed that daily AOH1996 treatment significantly reduced the tumor burden compared to controls. Additionally, combining AOH1996 with another widely used cancer drug, irinotecan, significantly increased the survival of xenograft-bearing mice compared to mice treated with either drug alone.

“Results have been promising,” Malkas added. “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.”

In further research, the team plan to investigate AOH1996’s mechanism of action to understand the drug better and improve ongoing clinical trials. “This study reports the anti-cancer activity of AOH1996 in a broad range of cancer cells and several animal tumor models,” they write in the paper. “We acknowledge that positive animal study results do not always translate into success in treating cancer patients. Future clinical studies are necessary to determine its efficacy for cancer treatment.”

“Taken together, our studies have characterized the unique molecular mechanisms of this now investigational new drug, which has entered Phase 1 clinical trials, and they have validated the drug’s unique mechanism of action by which inhibition of transcription–replication conflict resolution likely opens a new therapeutic avenue for the selective killing of cancer cells.”

Reference: Gu L, Li M, Haratipour P, et al. Small molecule targeting of transcription–replication conflict for selective chemotherapy. Cell Chem Biol. 2023. doi: 10.1016/j.chembiol.2023.07.001

This article is a rework of a press release issued by City of Hope. Material has been edited for length and content.