Posted on Aug 01, 2023, 3 p.m.
According to a report published in the journal Cell Chemical Biology, scientists at the City of Hope Hospital may have developed a molecule that eradicates all solid cancer tumors while leaving other cells intact and unaffected. The study, “Small Molecule Targeting of Transcription-Replication Conflict for Selective Chemotherapy,” suggests that the molecule has been effective during preclinical investigations in treating various cancer cells.
Mutated forms of PCNA assist cancer cells with growth and repair, this molecule, AOH1996 was developed to target and eradicate mutated PCNA. In the past PCNA was considered to be too challenging to target, but according to the researchers, this newly developed molecule represents the culmination of 20 years of work, annihilating all solid tumors in their preclinical research. This work is still ongoing, investigating mechanisms in animal models and there is also a Phase 1 clinical trial in humans.
“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,” says team leader Dr. Linda Malkas, a professor in City of Hope’s Department of Molecular Diagnostics and Experimental Therapeutics and the M.T. & B.A. Ahmadinia Professor in Molecular Oncology.
“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 investigational chemotherapeutic is currently in a Phase 1 clinical trial in humans at City of Hope,” says Malkas.
AOH1996 has been tested on over 70 cancer cell lines and several normal control cells in the current study, findings indicate that the molecule selectively killed cancer cells by disrupting their normal reproductive cycle to prevent cells with damaged DNA to divide thus stopping the replication of faulty DNA inducing apoptosis cell death without interrupting 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,” says Long Gu, Ph.D., 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 personalized, targeted cancer medicines,” said Gu.
“City of Hope has world leaders in cancer research. They also have the infrastructure to drive translational drug discovery from the laboratory into the clinic for patients in need,” says Daniel Von Hoff, M.D., study co-author and a distinguished professor at Translational Genomics Research Institute, part of the City of Hope.
Additionally, the researchers' experiments show that this molecule makes cancer cells more susceptible to agents that damage chromosomes and DNA which suggests that AOH1996 may also be useful in combination therapies and/or the development of new chemotherapeutics. Moving forward the team hopes that they will be able to enhance the ongoing clinical trials in humans with knowledge gained from their continued investigations of the mechanisms behind this promising cancer-killing pill.
AOH1996 is exclusively licensed by the City of Hope to RLL, LLC, a biotechnology company that Prof. Malkas co-founded and holds a financial interest in. Individuals interested in the Phase 1 clinical trial should review the eligibility requirements at clinicaltrials.gov. If eligible, call 626-218-1133 or visit the City of Hope’s clinical trials webpage.
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