Characterising and targeting Cyclin D stabilisation in development and disease.

The growth of organisms, and organs such as the brain, fingers and toes, occur by cells dividing and changing from simple precursors into complex cells with specific functions through a series of carefully regulated processes. The cell cycle controls cell division by requiring the cell to pass multiple checkpoints to ensure only a healthy cell can divide. Another important ability for a cell is to be able to stop dividing. When no more cells are required in the developing brain, cells exit the cycle resulting in no more cells being produced than are needed. Failure to exit the cell cycle can lead to excessive cell numbers, and so-called overgrowth disorders, whereby organs are too big and often do not have the correct structure. In the brain this results in the disorder megalencephaly. While brains generally stop growing once fully developed, the brains of people with overgrowth disorders continue to grow. This growth persists even after surgical intervention, resulting in further complications. Interestingly in over-growth syndromes, some patients, also have an extra finger and/or toe. Taken together, these observations tell us that precise management of the cell cycle is required for development of the brain and formation of limb digits.

The aim of this study is to investigate a family of proteins called D-type Cyclins (CCND), which act as a molecular switch for the cell cycle. This will help to understand the molecular processes that control the cell cycle and how these lead to developmental defects when they don't work correctly. When CCND levels are high, cells continue to divide to create more cells, however when CCND is switched off the cells stop dividing. I am interested in disorders that occur which CCND2 does not get switched off, meaning cells continue to divide even when they're not supposed to. In particular, I want to learn more about the molecules that control this switch, what happens in a cell when the switch cannot be turned off and to develop molecules that overcome high levels of CCND2 in order to stop the cells dividing. Using this information, I hope to learn how cells signal to stop cell division normally and therefore how they coordinate the development of complex structures such as the brain.

Currently there are no cures or therapies available that can overcome the post-natal effects of CCND2 stabilisation. In some cases surgery is attempted, but with limited success. As well as CCND2, other D-type Cyclins such as Cyclin D1 also cause disease, such as breast cancer, when they cannot be switched off. By gaining new insights into the mechanisms governing the cell cycle, my aim is to not only identify new disease genes which cause these conditions and understand the roles they play, but also develop novel treatments in order to improve the quality of life for patients and their families.

This project has the potential to impact on a number of different groups.

Patients: Little is known about the progression of overgrowth disorders, and how to manage the conditions clinically. This fellowship will therefore have demonstrable impact on patients by increasing knowledge about the causes of their disease, identifying novel disease genes and supporting genetic diagnostic testing. By developing novel therapeutics, this research aims to prolong survival and improve the quality of life for patients and their families by slowing or stopping disease progression. Somatic mutations in the pathway, the same mutations that cause megalencephaly related overgrowth syndromes, have also been implicated in myeloid leukaemias. By studying the effects of CCND2 stabilisation, we will likely gain novel insights into the mechanisms underlying ML, with the potential that novel therapies will benefit ML patients too. Furthermore, both CCND1 and CCND3 have been implicated in cancers, e.g. Breast cancer, therefore the knowledge and resources gained in this fellowship may impact these patients too.

Scientific and medical community: This work will be of interest to groups studying overgrowth disorders, the mTOR signalling pathway and cell cycle regulation by D-type Cyclins. Dysregulation of the cell cycle is the underlying cause of a wide range of major disorders including cancers and overgrowth syndromes. This work focusses on Cyclin D2, which I have already shown plays a crucial role in the development of the brain. While Cyclin D2 mutations are rare, I have found that mutations in any gene of the pathway leading to mTOR activation causes CCND2 stabilisation, therefore the findings from this study will reflect PI3K-AKT pathway activation not just CCND2. Furthermore, while development defects of the brain and limb digits are the key phenotypes observed with germline CCND2 mutations, other cells and tissues are also known to be affected such as the myeloid precursors and pancreatic B-cells. This fellowship will therefore be of interest to researchers studying myeloid leukaemias and hypoglycaemia.

Commercial sector: This fellowship aims to identify molecules that overcome stabilisation of D-type cyclins. Current therapies include those which inhibit specific molecules such as mTOR or those that inhibit cell cycle proliferation completely, such as CDK inhibitors. These therapeutics, however, are limited in their applicability (i.e. are mutation specific) or have unwanted secondary consequences (e.g. neutropenia). Understanding how D-type cyclins bind to CDK4 can give further insight into the mechanisms that drive cell cycle progression. Such insight has already been discovered through solving the CCND3-CDK4 and CCND1-CDK4 structures, identifying further regulators such as HSP90 and CDC37. The CCND2-CDK4 complex is the final complex of this family to be solved therefore the data generated will allow atomic level comparisons of the D-type Cyclin-CDK4 complexes and provide deeper understanding of these interactions. The data generated in this fellowship therefore has potential to support the development of a drug by a UK based company, interested in the next generation of CDK4 inhibitor therapies, which may ultimately be used around the world.

NHS: This work also aims to demonstrate the clinical utility and validity of integrated "systems medicine" annotation and its ability to make relevant predictions about disease causality. The development of a strong interface between developmental biology, functional annotation and diagnostic or translational development work is therefore an important benefit of this research to NHS Genomic Medicine Centres and ultimately the patients. By developing more effective frontline therapies, the NHS would benefit by performing less surgeries, reduced demand for clinical specialties (e.g. paediatric Neurology) and saving in costs for therapeutics which are not effective in many individuals.