New York: A team of US scientists have, in a major breakthrough, developed a novel cancer-stopping pill that can annihilate all solid tumours.
The pill, named AOH1996, has shown to be effective in pre-clinical research treating cells derived from breast, prostate, brain, ovarian, cervical, skin, and lung cancers.
Developed by a team at City of Hope in California, US, AOH1996 was named after Anna Olivia Healy, who was born in 1996 and died when she was just nine-years-old after being diagnosed with a rare childhood cancer neuroblastoma.
According to Linda Malkas, Professor in City of Hope’s Department of Molecular Diagnostics and Experimental Therapeutics, most targeted therapies focus on a single pathway, which enables wily cancer to mutate and eventually become resistant.
However, the cancer-killing pill that Malkas has been developing over the past two decades, attacks a protein called proliferating cell nuclear antigen (PCNA), which encourages tumours to grow by aiding DNA replication and the repair of cancerous cells.
“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, who published the findings in the journal Cell Chemical Biology.
Malkas noted that results in cell and animal models have been promising and Phase 1 clinical trial in humans is currently underway. “AOH1996 can suppress tumour growth as a monotherapy or combination treatment in cell and animal models without resulting in toxicity”.
The researchers tested AOH1996, a small molecule PCNA inhibitor, in more than 70 cancer cell lines and several normal control cells. They found that AOH1996 selectively kills cancer cells by disrupting the normal cell reproductive cycle. It targets something called transcription replication conflicts, which occur when mechanisms responsible for gene expression and genome duplication collide.
The investigational therapy prevented cells with damaged DNA from dividing in G2/M phase and from making a copy of faulty DNA in S phase. As a result, AOH1996 caused cancer cell death (apoptosis), but it did not interrupt 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 lead author Long Gu, 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,” Long said.
Interestingly, experiments showed that the investigational pill made cancer cells more susceptible to chemical agents that cause DNA or chromosome damage, such as the chemotherapy drug cisplatin, hinting that AOH1996 could become a useful tool in combination therapies as well as for the development of new chemotherapeutics.
