Funded by The Little Princess Trust and administered by CCLG
Lead investigator: Dr Karim Malik, University of Bristol
Award: £198,991.57
Awarded July 2021
Cancer cells are characterized by having too much of certain proteins (oncoproteins) or too little of others (tumour suppressor proteins) that control cell growth. This work focuses on defining how a new oncoprotein (called CARM1) we have discovered in neuroblastoma cells helps the cancer cells to survive, grow and avoid death. We have found that CARM1 is "enlisted" by the most well-known and characterised protein that causes the most lethal clinical subtype of neuroblastoma, that is MYCN. We have determined that MYCN raises levels of CARM1 in neuroblastoma cells, and CARM1 then ensures that the cancer cells acquire ways to survive the stresses and demands inherent in the rapid expansion of cancers. Thus, neuroblastoma cells with excessive MYCN become dependent on CARM1. We have confirmed that genetically eliminating CARM1 in neuroblastoma cells leads to growth inhibition and decreased survival of neuroblastoma.
Importantly, pharmaceutical companies have recognised the importance of proteins such as CARM1, which are known as epigenetic modifiers. Indeed, highly specific, and potent chemical inhibitors of CARM1 have recently been discovered. We obtained CARM1 inhibitors and examined whether they represent novel drugs for neuroblastoma. Encouragingly, our experiments show that inhibiting CARM1 has several beneficial effects, including interfering with the biological action of MYCN. These drugs also instigate an emergency cell survival response (known as autophagy) in neuroblastoma.
Importantly, we further demonstrate that when this survival response is disrupted (using CARM1 and autophagy inhibitors together), neuroblastoma cells die. The use of autophagy inhibitors in drug combinations is showing great promise in other lethal cancers such as pancreatic cancer, and these inhibitors are already clinically approved (such as chloroquine, widely used as an anti-malarial drug). We believe that using autophagy and CARM1 inhibitors together specifically targets neuroblastoma with excessive MYCN, and thereby represents a novel therapeutic approach for neuroblastoma.