New study shows potential of new cancer targeting combination

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The authors of a new study say it has revealed a potential benefit by combining endocytosis inhibitor drugs with immuno-oncology therapies.

Immuno-oncology therapies have emerged in recent years as targeted treatments that harness the bodies immune system to fight cancer cells.

They are highly effective in a proportion of cases - around 30 per cent - with the new study identifying a combination to increase the response rate. 

The study was a collaboration between researchers from the University of Queensland’s (UQ) Diamantina Institute and Institute for Molecular Bioscience, The Princess Alexandra Hospital, Children’s Medical Research Institute, The University of Newcastle, and The University of Sydney.

In preclinical models, they have discovered that compounds called endocytosis inhibitors (in particular, dynamin inhibitors), when used in combination with certain immuno-oncology therapies can increase the patient response rate by promoting drug-target availability on the surface of the tumour cells.

“Results in pre-clinical models are impressive,” said Professor Phil Robinson of the Children’s Medical Research Institute (CMRI).

The researchers said immuno-oncology therapies work by binding to specific receptors on the surface of cancer cells. This activates the patient’s own immune response to recognise and selectively kill the tumour. However, if the majority of target receptors for the cancer drug are internalised and are not located on the cell surface when the cancer treatment is administered, the therapy is either ineffective or patients respond poorly.

"In pre-clinical models, the addition of an endocytosis inhibitor reduces/prevents this internalisation and increases the exposure of target receptors on the tumour cell surface for the immuno-oncology therapy to bind," they said.

“Our collaborators at UQ have shown in the pre-clinical setting that dynamin inhibition improves immune cell mediated killing of tumour cells (Antibody-Dependent Cellular Cytotoxicity) for three separate immunotherapies, cetuximab (anti-EGFR), trastuzumab (anti-HER2), and avelumab (anti-PD-L1). The UQ data shows in pre-clinical models in vivo that the combination therapy reverses resistance to the immune-oncology drug (kills the tumour) and induces resistance to rechallenge with new tumours (i.e., provides long-term protection) without further therapy,” said Professor Robinson.

“The Cell data are also proof of principle that treatment of patients with a dynamin inhibitor can prevent internalisation of receptors on tumours in patients. We now know that there are existing endocytosis inhibitor drugs whose off-target effects can be used and tested in future trials. Our focus is to develop the next generation of these drugs, which will be more specific, more potent, with fewer side-effects - and which can reach more people.”

The researchers said their study was based on the use of prochlorperazine. It is a well-known drug, which has been on the market for many years, that has endocytosis inhibition properties (specifically through dynamin inhibition) and is currently licensed for other indications.

Professor Robinson said researchers at CMRI and the University of Newcastle have been working for over a decade on a new class of endocytosis inhibitor drugs that are designed to be more potent and specific than prochlorperazine.

“Now, we just need to prove its efficacy in rigorous Phase II trials and get our new candidate dynamin inhibitor drugs into the clinical pipeline,” said Professor Robinson.