A “revolutionary” molecule that kills all solid cancerous tumors and leaves other cells intact has been developed by scientists.
The team from City of Hope, one of America’s largest cancer research and treatment organizations, has made a breakthrough against a protein called PCNA.
A mutated form of the protein helps cancers repair themselves and grow. The team developed a molecule, AOH1996, which targets and kills the mutated PCNA.
PCNA was previously considered too difficult to be a therapeutic target, but AOH1996 appears to wipe out all solid tumors in preclinical research.
The experimental chemotherapy is currently being tested on humans in a Phase 1 human clinical trial at City of Hope, and scientists are still trying to study precisely how the the pill that stops cancer works.
Researchers found that the pill stopped cells with damaged DNA from dividing and making a copy of the faulty DNA, causing cancer cells to die, known as apoptosis, but it did not interrupt not healthy stem cells.
The new therapy stems from 20 years of research and development and targets a cancerous variant of PCNA, a protein which, in its mutated form, is essential for DNA replication and the repair of all expanding tumors.
Dr. Linda Malkas, Professor in the Department of Molecular Diagnostics and Experimental Therapeutics at City of Hope and MT & BA Ahmadinia Professor in Molecular Oncology, leads the team.
She explained how the molecule selectively disrupts DNA replication and repair in cancer cells, leaving healthy cells intact.
She said: “Most targeted therapies focus on a single pathway, which allows tricky cancer to mutate and eventually become resistant.
“PCNA is like a major air terminal hub containing multiple aircraft gates.
“The data suggests that PCNA is uniquely modified in cancer cells, and this fact allowed us to design a drug that only targets the form of PCNA in cancer cells.
“Our cancer pill is like a blizzard shutting down a key airline hub, halting all inbound and outbound flights only on planes carrying cancer cells.”
Dr Malkas said results so far were “promising” as the molecule can suppress tumor growth alone or in combination with other cancer treatments “without causing toxicity”.
The study, published in the journal Cell Chemical Biology, claims that AOH1996 has been effective in preclinical research treating cells derived from cancers of the breast, prostate, brain, ovary, cervix, skin and lung.
The researchers tested AOH1996 in over 70 cancer cell lines and several normal control cells.
They discovered that the molecule selectively kills cancer cells by disrupting the cells’ normal reproductive cycle.
In their research, they found that it prevented cells with damaged DNA from dividing and making a copy of the faulty DNA, causing cancer cells to die, known as apoptosis, but it didn’t. didn’t interrupt healthy stem cells.
Dr. Long Gu, Associate Research Professor, co-author of the study, said: “No one has ever targeted PCNA as a therapeutic because it was considered ‘indrugable’, but it is clear that City of Hope was able to develop an experimental drug for a difficult protein target.
“We found that PCNA is one of the potential causes of increased nucleic acid replication errors in cancer cells.
“Now that we know the problem and can inhibit it, we will dig deeper to understand the process of developing more personalized and targeted cancer drugs.”
Experiments have shown that the experimental pill makes cancer cells more sensitive to chemical agents that cause DNA or chromosome damage, suggesting that AOH1996 could be useful in combination therapies and new chemotherapies.
Another co-author, Professor Daniel Von Hoff, added: ‘City of Hope has world leaders in cancer research. They also have the infrastructure to drive translational drug discovery from the lab to the clinic for patients who need it.
In a next step, researchers will seek to better understand the mechanism of action in order to further improve the ongoing clinical trial in humans.
City of Hope’s groundbreaking translational research history includes the development of the technology underlying synthetic human insulin and monoclonal antibodies, which are integral to widely used and life-saving cancer drugs, such as trastuzumab, rituximab and cetuximab.
AOH1996 is exclusively licensed by City of Hope to RLL, LLC, a biotechnology company that Professor Malkas co-founded and in which he has a financial interest.
