A ‘cure for cancer’ has long been something of a holy grail for medical research – but experience has shown that cancers are highly individualised and respond differently to therapy, adapting to resist them. Now, in an early study, researchers have tested a cancer drug that kills all solid cancer tumours while leaving other cells unharmed and resulting in no toxicity. The new molecule targets a common key cancer cell protein, the proliferating cell nuclear antigen (PCNA), that is key to helping them grow and metastasise – a target previously believed to be ‘undruggable’.
The new drug, AOH1996, was tested in vitro against 70 different cancer cell lines, including breast, prostate, brain, ovarian, cervical, skin, and lung cancer. It proved effective against all of them, as well as sparing healthy cells. What’s more, developing resistance against the drug is unlikely due to the nature of PCNA as a mistranslation rather than a mutation. The results were published in Cell Chemical Biology. Instructions for synthesis were included in supplementary material.
The last great breakthrough in cancer treatment was immunotherapy, and since then cancer research has looked for the next big leap. A search of journal articles in the Pubmed database showed that “cancer” has grown from 6% of all results in 1950 to 16% by 2016. More recent development in cancer therapies has included gene-based approaches, naked nucleic acids based therapy, targeting micro RNAs, oncolytic virotherapy, suicide gene based therapy, targeting telomerase, cell mediated gene therapy, and CRISPR/Cas9 based therapy.
Shutting down the hub
The research was led by Dr Linda Malkas, a professor at City of Hope Hospital, who said that the molecule selectively disrupts DNA replication and repair in cancer cells, leaving healthy cells unaffected. Animal models also showed a reduction of tumour burden with no apparent adverse effects, with the no observed adverse effect level (NOAEL) calculated being six times higher than the administered dose.
She explained the drug in simple terms to the Daily Mail: “Most targeted therapies focus on a single pathway, which enables wily cancer to mutate and eventually become resistant,” she said. “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.”
Dr Malkas said results so far have been ‘promising’ as the molecule can suppress tumour growth on its own or in combination with other cancer treatments without resulting in toxicity.
The development of AOH1996 is the culmination of nearly two decades of work by City of Hope Hospital in Lose Angles.
Decades in the making
PCNA in breast cancer was identified as a potential target in 2006 since it is an isomer, allowing antibodies to target it. The researchers’ first attempts with antibodies to target PCNA were unsuccessful as these were too big to penetrate into solid tumours. Next, they tried a small molecule, which appeared to work in vitro but in vivo proved to have a half-life of only 30 minutes. But they were able to tweak that molecule and arrive at the current drug, AOH1996. It was named after Anna Olivia Healy who died in 2005 from neuroblastoma, and she became the inspiration for the research.
“She died when she was only 9 years old from neuroblastoma, a children’s cancer that affects only 600 kids in America each year,” Malkas said. “I met Anna’s father when she was at her end stages. I sat him down for two hours in my office and showed him all of my data on this protein I had been studying in cancer cells.”
At the time, Dr Malkas was researching breast cancer, studying a protein found in cancer cells but not normal cells. Dr Malkas eventually took Anna’s father, Steve, and his wife, Barbara, to see her lab.
“[Steve] asked if I could do something about neuroblastoma and he wrote my lab a cheque for $25 000,” Dr Malkas said. “That was the moment that changed my life – my fork in the road. I knew I wanted to do something special for that little girl.”
