Core-Modelling tumour development and therapy

Lung cancer is the leading cause of cancer-related death worldwide. Most patients present with locally advanced inoperable or metastatic disease and despite advances in treatment median survival at this stage remains low. While new therapies for the treatment of advanced lung cancer are showing promising results recent studies suggest that tumours harbouring Kras mutations (30-50% of non-small cell lung cancers) may be particularly difficult to treat. Therefore, novel therapeutic strategies aimed at Kras mutant lung tumours are urgently in need. Our lab is interested in the mechanisms responsible for the progression of lung tumours harbouring Kras mutations. By understanding the processes that enable tumours to develop we aim to find new vulnerable points for therapeutic intervention. Using mouse lung tumour models we recently showed that a Kras-mutation is sufficient to drive the initial expansion of tumour cells but progression to malignancy is associated with the acquisition of new mutations. We will now identify these additional requirements by mapping all mutations associated with benign and malignant disease using state-of-the-art whole genome sequencing technology. Furthermore, we will test the relevance of such mutations for tumour progression in vivo using mouse lung tumour models. Finally, we will use our models to test the therapeutic potential of targeting these mutations in established lung tumours with mutant Kras.

The Ras/MAPK-signalling pathway plays a pivotal role in cell proliferation, differentiation and cell survival and is frequently deregulated in human cancer. Kras missense mutations (codons 12, 13 and 61) are particularly prevalent in lung, pancreas and colon tumours and result in the accumulation of constitutively active, GTP-bound Kras protein. Lung cancer is the leading cause of cancer-related death worldwide. Most patients present with locally advanced inoperable or metastatic disease and despite advances in treatment median survival at this stage remains low. While targeted therapies for the treatment of advanced lung cancer are showing promising results recent studies suggest that tumours harbouring Kras mutations may pose an increased therapeutic challenge by failing to respond to anti-EGFR therapies. With no currently available Ras-targeted therapies and limited success targeting other pathway members, novel therapeutic strategies aimed at these tumours are urgently in need. Our lab is interested in the molecular mechanisms responsible for lung tumour progression in the presence of a Kras-mutation and in using pre-clinical models to establish the therapeutic potential of targeting such evolutionary requirements in established tumours. To identify and pre-clinically validate novel therapeutic strategies for the treatment of these tumours we start by generating genetically modified mouse models in which human lung tumour development can be closely recapitulated. Using such regulatable models we characterize the spontaneous mutations that accompany each stage of tumour evolution and in parallel, test the impact of acute genetic changes in disease progression and tumour maintenance. Our recent data indicate that Kras oncogenic activation is sufficient to drive tumour initiation but an increase in Ras/MAPK-pathway signalling is required for malignant progression. In turn, p53 activation (and its counter-selection) is only triggered by this secondary increase in Ras/MAPK signalling and is therefore absent in benign stages of disease. One of our major goals is to define the molecular mechanisms responsible for malignant progression in KrasG12D-driven lung tumours. To achieve this we are carrying out a genome-wide screen in laser-captured tumour material in collaboration with Dr. David Adams (Sanger Institute). Next-generation sequencing and copy number data from low grade and high grade lung tumour areas (from individual tumours) will be compared to identify potential biomarkers and novel targets for therapeutic intervention. Our second aim is to develop new switchable mouse models to test the impact of candidate mutations in lung tumour evolution and their potential as therapeutic targets. Presently, we are developing new models to test the role of p53 mutations and Kras copy number changes in tumour progression and maintenance. Our future goal is to develop regulatable mouse models of promising therapeutic targets identified in our screen in order to model their therapeutic potential in KrasG12D lung tumours.