Investigating why Cdk4/6 inhibitors have durable long-term effect on tumour growth.

This proposal will address how Cdk4/6 inhibitors, which have shown remarkable efficacy at treating metastatic breast cancer, cause a durable long-term cell cycle arrest. We will perform live-cell imaging with cell cycle reporters to accurately measure drug-responses in individual cells. Our preliminary work in healthy diploid cells, demonstrates that they arrest reversibly over the first few days before withdrawing into a state of irreversible cell cycle arrest. We will investigate the molecular pathways that control this switch in reversibility and we will also determine whether it is triggered quicker in cancer cell lines that respond better to Cdk4/6 inhibition. Finally, we will use phenotypic screening to search for novel ways to improve long-term arrest following Cdk4/6 inhibition.

Predicted Outcomes
The expectation is that these studies will help to explain: 1) why Cdk4/6 inhibitors are so effective in the clinic; 2) what tumour genotypes will benefit from Cdk4/6 inhibition (i.e. to help develop a precision medicine strategy); and 3) what combinations treatments can produce a durable long-term response to Cdk4/6 inhibition.

Training
This translational project will allow the student to receive interdisciplinary training at the interface between molecular and cellular biology, high-content microscopy with quantitative computational analysis, and phenotypic drug screening.

Questions:

1. Explain interdisciplinary interface: Quantitative approaches will be developed to allow automated cell cycle analysis in individual cells. This will be used as a basis for a translational phenotypic screening program to find combination strategies to improve the long-term effects of Cdk4/6 inhibitors. Student will also use a variety of molecular and cell biology skills to analyse the pathways the determine the response to Cdk4/6 inhibition.

2. Does project require significant amount of quantitative skills? YES

3. Does project require significant amount of whole organism physiology skills? NO