Dr Michelle Garrett

One of the principal characteristics of human cancer is uncontrolled cell proliferation through deregulation of the cell division cycle. We now know that signalling pathways can act on the cell division cycle: for example, through growth factor mediated signalling or through activation of cell cycle checkpoints in response to DNA damage. We are therefore interested in the relationship of these pathways to the cell division cycle and how both may be targeted for the treatment of cancer.

In the Cell Cycle Control Team, we are currently involved in a number of drug discovery projects on targets that regulate cell signalling, cell cycle checkpoints and DNA repair. These include the serine/threonine kinases PKB /AKT, CHK1 and CHK2, and a novel DNA repair target. A key role of the team in this activity is to understand, at the molecular level, the mechanism of action of compounds discovered on these projects—both in vitro (in cell lines) and in vivo. For example, for the PKB/AKT drug discovery project we have investigated the effects of project compounds on the phosphorylation status of known substrates of PKB/AKT, including GSK3beta, PRAS40 and FOXO1. Such potential markers of drug effect are often referred to as pharmacodynamic (PD) biomarkers and are becoming established as an important part of both preclinical drug discovery and clinical drug development.

A further aim of the team is to use the small molecules developed on these drug discovery projects as chemical probes for further target-based research. A key focus of this research is the identification of potential mechanisms of resistance that these small molecules may generate in the clinic. We are also using project compounds to probe the pathways we are targeting and their relationship with one another in cancer. For example, we are currently using small molecule inhibitors discovered on the PKB/AKT and CHK1 projects as chemical probes to investigate how growth factor dependent cell signalling pathways may regulate cell cycle checkpoints, which may lead to new target identification and thus new drug discovery.

We have also used our small molecules as tools to develop novel pharmacodynamic (PD) biomarker assays for late stage preclinical and early stage clinical evaluation of compounds. This research has led to the recent establishment of the Clinical PD Biomarker Group, within the Cell Cycle Control Team. The Group’s objectives are to develop and implement fit-for-purpose assays for the evaluation of PD biomarkers in Phase I clinical trials of new anticancer agents. The establishment of this group provides the opportunity for proof of mechanism studies of molecular targeted agents in the Phase I setting and to determine whether there is evidence that such assays may act as predictors of patient response. Whilst research to date has focussed on adult Phase I trials, a future avenue is the translation of these biomarkers into the paediatric setting.

Key Aims

• To discover and develop new drugs that act on molecular components of the cell division cycle, and its associated pathways, and to understand the mechanism of action of these drugs.
• To use the small molecules discovered on drug discovery projects as chemical probes to facilitate further research on our drug targets.
• To identify and develop PD biomarkers to be used in both preclinical drug development and Phase I clinical trials of our new molecular targeted anticancer agents.

Dr Michelle Garrett specialises in the discovery and development of novel molecular targeted agents for the treatment of cancer.

One of the principal characteristics of human cancer is the ability of cells to proliferate in an uncontrolled manner. At the heart of this is the cell division cycle and when not controlled correctly, it can be one of the underlying causes of cancer. Dr Garrett and her team are particularly interested in how the cell division cycle and the mechanisms by which it is controlled may be targeted for the treatment of cancer.

This research drives the drug discovery projects, which Dr Garrett and her team are currently involved with and include the AKT/PKB signalling kinase and the cell cycle checkpoint kinases CHK1 and CHK2. These drug discovery activities have recently led to the identification of a novel small molecule therapeutic that has now entered Phase I clinical trials for evaluation in patients with a range of cancer types

Dr Garrett received her undergraduate degree from the University of Leeds and then joined the ICR, as a PhD student, gaining a PhD in cancer cell signalling. She then won a Lucille Markey International Research Fellowship and in 1991 moved to the USA to undertake post-doctoral studies at Yale University School of Medicine. In 1994 Michelle joined Onyx Pharmaceuticals, California, USA, where she went on to become a team leader involved in the development of cancer drugs targeting the cell division cycle. In 1999 Michelle returned to The ICR [ The or the ] to take up a team leader position in the Cancer Research UK Cancer Therapeutics Unit. Dr Garrett says that “returning to the ICR has given me the unique opportunity to undertake drug discovery in an academic setting. This allows me to interact on a day-to day basis with both clinicians and other researchers; interactions with both groups are vital to cancer drug discovery.

Outside of work Michelle likes cooking and reading—in particular, science fiction—and she also enjoys the outdoors, including gardening, camping and skiing.