Manuela Callari
An Australian cancer researcher has repurposed an inexpensive medication typically used in hospitals to treat nausea to improve the response of expensive anti-cancer antibodies and get the patient’s own immune cells on the job of tumour killing.
Treating cancer is like trying to get into a house where the front door is locked, says Emma-Anne Karslen, a General Surgery registrar undertaking her PhD at The University of Queensland’s Frazer Institute Simpson Lab, speaking at the Falling Walls Science Summit in Berlin.
Conventional chemotherapy is highly effective – you do get inside, but you damage the whole building in the process. Monoclonal antibody therapy, instead, is more like a key to the lock. It offers targeted treatment – the key – that directly attaches to receptors on the cancer cell surface – the lock – to kill that cell alone, says Karslen, who won first place at the 2023 Falling Walls Lab Brisbane last August and ended third at the Berlin’s Summit.
Monoclonal antibody therapy for cancer is a type of treatment that uses artificially created antibodies to target specific molecules found on cancer cell membranes. Antibodies are proteins the immune system produces to identify and neutralise harmful substances like viruses or abnormal cells.
In cancer therapy, scientists design monoclonal antibodies in a lab to recognise and attach themselves to certain proteins on cancer cell membranes. When these antibodies bind to the cancer cells, they can stop their growth; signal the immune system to attack them; or deliver treatments directly to the cancer cells. This precision helps in sparing healthy cells from damage often caused by traditional treatments like chemotherapy, but effectiveness varies depending on the type of cancer and individual response.
Karslen says only 15 to 30% of patients respond to it when used as a monotherapy. Survival rates slightly improve when antibody therapy is used in combination with radiotherapy or chemotherapy, sometimes reaching 30 to 40% response rates. And the costs are substantial, with Australia alone spending up to $355 million yearly on non-responders.
“Haven’t we all had a dodgy lock?” Karslen asks. “It’s the right key, but for some reason, that door won’t open no matter how many times you jiggle it.”
Identifying why some patients have a “dodgy lock” or fail to respond to monoclonal antibodies has been a significant challenge. Now, researchers from The University of Queensland (UQ) have uncovered a crucial clue.
They found that a protein called epidermal growth factor receptor (EGFR) behaves differently in some tumours.
EGFR protein is crucial for normal skin development and balance. However, when it doesn’t function properly, it can lead to issues like excessive cell growth; problems with wound healing; psoriasis-like skin problems; hair follicle defects; and the formation of tumours.
Because of its role in cancer development, researchers have designed drugs to inhibit EGFR. But treatments targeting it haven’t worked well.
Secret agent protein in battle against cancer
EGFR can either stay on the membrane of cancer cells or be internalised through endocytosis – a cellular process where cells engulf molecules. The University of Queensland’s researchers used advanced imaging techniques like confocal microscopy to watch how EGFR behaved in mice and human skin tumour samples. In advanced tumours, they saw that EGFR didn’t always go through its usual endocytosis process, an irregularity which made anti-EGFR treatment work better.
This discovery led them to explore the idea of temporarily stopping endocytosis using a drug called prochlorperazine (PCZ), which is already used in hospitals for nausea and vomiting. “We found a locksmith,” says Karlsen.
“And to our delight, we even saw a regression of metastatic disease that was previously refractory to even our best chemotherapies….”
Karslen
PCZ keeps EGFR on the cancer cell surface and facilitates more effective attachment of monoclonal antibodies targeting EGFR. In addition, the prolonged exposure of EGFRs on the cell surface promotes a robust immune response, contributing to the clearance of the tumour by the patient’s own immune system.
In an ongoing safety trial that involved 12 patients with HER2-positive metastatic breast cancer, researchers showed that combining PCZ with monoclonal antibody therapies had no significant adverse effects. “And to our delight, we even saw a regression of metastatic disease that was previously refractory to even our best chemotherapies,” says Karslen.
The UQ researchers are now extending this research into other cancers and recruiting for a clinical trial to explore the combination of PCZ with trastuzumab, a medication used to treat HER2-positive breast cancers in a larger cohort of patients.
“To really see the long-term effects of the combination therapy would take a couple of years,” says Kerslen. “So realistically, within the next five years, we could start seeing this [treatment] incorporated into [clinical] practice.”
“We are breaking down the wall of monoclonal antibody resistance for the 70% of patients who are currently non-responders,” she said at the end of her speech in Berlin. “And my favourite part of this is that it won’t be through the generation of a novel medication that will cost tens of millions of dollars in R&D and a significant environmental impact, but rather through reaching into our own pharmacies and repurposing an already PBS-approved medication that costs just $20 a vial.”