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Activating c-Cbl gene causes immune system to attack cancer cells

Upregulation of the c-Cbl gene causes degradation of the immune checkpoint protein PD-1 and may provide a possible new avenue for cancer therapies, according to researchers.

Researchers from Boston University School of Medicine, US have revealed that c-Cbl, a gene coding for the E3 ubiquitin-ligase, is a negative regulator of cell surface signalling that can degrade the protein PD-1 and promote T-cell attacks on cancer cells.

PD-1 is an immune checkpoint protein that  recognises body tissues as belonging to the host and inhibits T-cell activation against them.  Cancer cells regularly over-express PD-1 and therefore silence the immune system challenging them. The scientists suggest that manipulating c-Cbl’s ability to regulate expression of PD-1 may be beneficial in the treatment of certain cancers including melanoma, bladder, kidney, breast and non-small-cell lung cancers.

By comparing the growth of implanted tumours in a model modified to be missing one copy of the c-Cbl gene and a control with both copies of c-Cbl, researchers examined the effect of the gene on immune cells, finding that tumour growth was greater in the modified model.

 

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The team hope it may soon be possible to develop therapies that will inhibit tumour growth by upregulating c-Cbl and promoting E3 ubiquitin-ligase activity.

“While drugs targeting PD-1 are currently available for clinical use and such agents command a global market cap of more than $3 billion, only a small fraction of cancer patients respond to them. This trend suggests a need for agents that work simultaneously on more than one cancer-causing mechanism. Activating c-Cbl will degrade several proteins that contribute to tumour formation allowing the effects of its actions to go above and beyond PD-1 medications alone,” explained Vipul Chitalia, MD, PhD, corresponding author and associate professor of medicine at Boston University School of Medicine.

These findings appear in Scientific Reports.

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