Development of Beta-arrestin 2 small molecule inhibitors for brain cancer therapy
Cancers of the intracranial (IC) compartment carry unique therapeutic challenges and offer grim outcomes, regardless of tissue type. These cancers include primary malignancies, such as universally lethal glioblastoma (GBM), as well as far more common brain metastases. Our group unveiled the ability of IC tumours to cause a dramatic plunge in the number of circulating T-cells, the main cells that help drive the body’s defences against cancer. Immunotherapy is a novel modality of cancer therapy that has gained momentum in recent years, which works by harnessing and ramping up the body’s own immune system, especially T-cells (the immune system’s effector arm) to fight cancer. However, without T-cells, there is nothing for immunotherapy to act upon. Our group tracked the missing T-cells in patients with IC cancers and discovered them ‘trapped’ in the bone marrow. We showed that this phenomenon is accompanied by loss of sphingosine 1-phosphate receptor 1 (S1P1) from the T-cell surface. S1P1 is a molecule which would normally act as an ‘exit visa’ allowing T-cells to exit from the bone marrow. Without surface S1P1, T-cells instead are locked in, unable to circulate out of the marrow. To solve this problem, our group demonstrated that mice lacking Beta-arrestin 2 (βARR2), an adaptor protein responsible for S1P1 internalisation, do not experience sequestration, and their T-cells are instead able to travel to the brain, and, with the help of immunotherapy, fight their cancers. Our studies in mouse models provided the proof of concept that blocking βARR2 and preventing loss of S1P1 could promote T-cells travelling to the brain to produce anti-tumour responses. However, we’ve now found that inhibiting βARR2 does far more to combat cancer, and we’re finding unprecedented responses against many types of cancer when we knock out βARR2. We think we’ve uncovered an entirely novel cancer therapeutic, and we’ve partnered with a Nobel Laureate who is an expert in this molecule to help develop a pharmacological strategy to block βARR2. We hope that our continued work will allow for the development of more effective immunotherapies for patients with brain cancer.