After two decades of development, a new pill has shown to be effective in treating multiple cancers, including breast and prostate, with the scientists – from a leading US hospital – saying it kills solid tumours through “targeted chemotherapy”.
Likened to a “snowstorm that closes a key airline hub, shutting down all flights in and out only in planes carrying cancer cells”, the protein was developed by a research team at the City of Hope, one of the largest cancer research and treatment organisations in America.
The AOH1996 molecule works by targeting a cancerous variant of PCNA, a protein critical to DNA replication and repair of enlarging tumours, reports The Independent, and the investigational chemotherapeutic is currently in a phase one clinical trial in humans at City of Hope.
The team said it has shown to be effective in pre-clinical research treating breast, prostate, brain, ovarian, cervical, skin and lung cancers.
The study, published in the journal Cell Chemical Biology, tested the protein across more than 70 cancer cell lines. The results noted that AOH1996 selectively killed cancer cells by “disrupting the normal cell reproductive cycle”, with the next stage aiming to further the clinical trial in humans.
“Data suggest PCNA is uniquely altered in cancer cells, which allowed us to design a drug that targeted only the form of PCNA in cancer cells,” said Linda Malkas, PhD, professor in City of Hope’s Department of Molecular Diagnostics and Experimental Therapeutics and the MT & BA Ahmadinia Professor in Molecular Oncology.
“Results have been promising. AOH1996 can suppress tumour growth as a monotherapy or combination treatment in cell and animal models without resulting in toxicity. The investigational chemotherapeutic is currently in a phase one clinical trial in humans.”
“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,” said Long Gu, PhD, lead author of the study and an associate research professor in the Department of Molecular Diagnostics and Experimental Therapeutics at Beckman Research Institute of 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 personalised, targeted cancer medicines.”
Study details
Small Molecule Targeting of Transcription-Replication Conflict for Selective Chemotherapy
Long Gu, Caroline Li, Linda Malkas, et al.
Published in Cell Chemical Biology on 1 August 2023
Summary
Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes. Through a rational drug design approach, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner. Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1’s PCNA-binding region, confers resistance to AOH1996. Orally administrable and metabolically stable, AOH1996 suppresses tumour growth as a monotherapy or as a combination treatment but causes no discernable side effects. Inhibitors of transcription replication conflict resolution may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability.
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