Our molecular understanding of apoptosis, the prototypical cell death pathway, has led to the development of multiple clinically important cancer therapeutics. The fact that apoptosis represents just one of many molecularly distinct pathways used by cells to orchestrate their death suggests that many more clinically relevant targets and molecular therapeutics remain to be discovered. However, the availability of specific cell death programs are dependent on the cell context and the presence of the right stimulus. Therefore exploiting any pathway will require pinpointing the relevant context and the molecular mechanism that underpins its activation.

Our laboratory has developed an innovative genetic tool to reversibly inactivate the p53 tumor suppressor in the context of autochthonously arising cancers in the mouse. We have used this tool to inactivate p53 in an important model of small cell lung cancer (SCLC)—the deadliest form of lung cancer. Once reactivated in the model, p53 orchestrates a non-apoptotic cell death mechanisms that is dependent on the activity peptidyl-proline isomerases called cyclophilins. How cyclophilins modulate p53 biology and why this is required in certain contexts remains unclear.

In this project, we employ cell biology, genomics, structural biology, and biochemistry approaches. Please contact David to learn more about joining this team.