Scientists have developed a ‘breakthrough’ molecule that kills all solid cancerous tumors and leaves other cells untouched.
The team at the City of Hope, one of America’s largest cancer research and treatment organizations, has created a drug that targets a protein present in most cancers and helps them multiply in the body.
It is important because this protein was previously thought to be ‘unusable’ due to its structural and functional characteristics, making it a difficult target for drug development.
The experimental chemotherapeutic drug is currently being tested in humans in a phase 1 human clinical trial at City of Hope, and scientists are still trying to investigate exactly how the cancer stopping pill works.
The researchers found that the pill prevented cells with damaged DNA from dividing and making a copy of defective DNA, causing cancer cell death known as apoptosis, but it did not interrupt the healthy stem cells.
The new therapy is the result of 20 years of research and development and targets a cancerous variant of PCNA, a protein that, in its mutated form, is critical in DNA replication and repair of all expanding tumors, helping cancer to recover and grow.
The team has developed a molecule, AOH1996, that targets and kills the mutated PCNA. In preclinical studies, the treatment appears to destroy all solid tumors.
Dr. Linda Malkas, Professor in the Department of Molecular Diagnostics and Experimental Therapeutics at City of Hope and the MT & BA Ahmadinia Professor of Molecular Oncology lead the team.
She explained how the molecule selectively disrupts DNA replication and repair in cancer cells, leaving healthy cells unaffected.
She said: ‘Most targeted therapies focus on a single pathway, which allows devious cancers to mutate and eventually become resistant.
‘PCNA is like the hub of a large aviation terminal with multiple aircraft gates.
‘Data suggest that PCNA is uniquely altered in cancer cells, and this fact enabled us to design a drug that targeted only the form of PCNA in cancer cells.
“Our cancer-killing pill is like a blizzard that closes a major airline hub and halts all inbound and outbound flights on aircraft carrying cancer cells.”
Dr. Malkas said the results so far are “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 in the treatment of cells derived from breast, prostate, brain, ovarian, cervical, skin and lung cancers.
The researchers tested AOH1996 in more than 70 cancer cell lines and several normal control cells.
They found that the molecule selectively kills cancer cells by disrupting cells’ normal reproductive cycle.
In their study, they found that it prevented cells with damaged DNA from dividing and making a copy of defective DNA, which caused cancer cell death known as apoptosis, but it did not interrupt healthy stem cells.
Study co-author, Associate Professor Dr Long Gu, said: “No one has ever focused on PCNA as a therapeutic because it was considered “non-medicatable”, but City of Hope was clearly able to deliver a … to develop an investigational drug for a challenging protein target.
‘We discovered that PCNA is one of the possible 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 drugs.”
Experiments showed that the experimental pill made cancer cells more susceptible to chemical agents that cause DNA or chromosome damage, suggesting that AOH1996 could be useful in combination therapies and new chemotherapeutics.
Another co-author, Prof. Daniel Von Hoff, added: ‘City of Hope has world leaders in cancer research. They also have the infrastructure to take translational drug discovery from the lab to the clinic for patients in need.”
As a next step, the researchers will try to better understand the mechanism of action to further improve the ongoing human clinical trial.
City of Hope’s pioneering translational research history includes developing the technology underlying synthetic human insulin and monoclonal antibodies, which are an integral part of widely used, life-saving cancer drugs such as trastuzumab, rituximab and cetuximab.
AOH1996 is licensed exclusively by City of Hope to RLL, LLC, a biotechnology company that Prof Malkas co-founded and has a financial interest in.