Apoptosis

Cellular fate is controlled by multiple molecular pathways. The most studied is apoptosis, a form of programmed cell death used by all multicellular organisms to eliminate cells which are damaged, no longer needed or which might become a threat to the organism. This process is often deregulated in cancer cells allowing them to survive and proliferate when otherwise they should be eliminated.

BH3 mimetics

Dysfunctional apoptosis can cause or accelerate cancer development but also underlies resistance to common cancer treatment approaches such as chemotherapy. Members of a particular family of proteins (the “BCL-2” proteins) are critical regulators of apoptosis. A class of drugs called “BH3 mimetics” has now been developed to target some BCL-2 proteins and activate apoptosis, leading to tumour cell death. Whilst these drugs have shown success in some blood cancers, we have been investigating them to improve patient responses in a range of solid cancers, including melanoma, colorectal cancer mesothelioma and pancreatic cancer, amongst others.

Autophagy

Autophagy is a process that enables cells to survive under stressful conditions. Like apoptosis, it can also become dysfunctional in cancer. We recently showed that a critical autophagy regulator, that functions as a tumour suppressor, is also essential for the maintenance of gut cells and potentially the prevention of diseases such as inflammatory bowel disease (IBD). We are now exploiting our novel models of autophagy deficiency to determine how autophagy regulates immune responses to tumours and to develop novel therapies to counter unwanted gastrointestinal side-effects of cancer immunotherapy.