Approximately 320,000 patients are diagnosed with some form cancer in the UK each year. Despite improved therapies, half of these patients still die of their disease, usually after the failure of anticancer drug treatment. To date, mechanisms of drug resistance and also determinants of treatment toxicity which varies significantly between individual patients are poorly understood. Recent advances in molecular profiling techniques allow the comprehensive interrogation of large numbers of genes, transcripts and proteins which may be altered and contribute to progression and drug resistance in tumour tissues.
These technologies, including genome wide RNA expression and methylation profiling and DNA sequencing can be used to analyse the causes of cancer drug resistance in detail and this information can subsequently be used to develop better cancer drugs which prevent or overcome resistance and prolong patient survival. Furthermore, molecular studies can help to understand why some patients develop excessive toxicities during treatment with drugs which are well tolerated by most patients. This could help to develop tests that predict which individual patients will not tolerate a specific drug.
Importantly, we recently demonstrated that individual human tumours can contain highly heterogeneous cancer cell populations, for example good and poor prognosis cancer cells within the same tumour. This intratumour heterogeneity may have hampered the identification of markers of drug sensitivity or tumour aggressiveness in the past as single tumour biopsies are unlikely to reveal this complexity. Thus, our project uses our established sample collection protocols to comprehensively sample surgical specimens. This will allow the analysis of intratumour heterogeneity and its impact on outcome which is an urgent clinical need.
Tumour tissues can also change their molecular characteristics over time, for example during treatment, which mandates the longitudinal collection of tissue and blood specimens in order to understand how treatment resistance develops. We and others have recently shown that blood samples can be used to obtain information about tumour progression without the need for rebiopsies (Gerlinger, unpublished results and Forshew et al. Sci Transl Med 2012, 4:136ra68). Our aim is to regularly collect blood specimens from which tumour DNA and tumour cells can be extracted and studies as a surrogate of the tumour lesions. Taken together, multiregion sampling of tumours at surgery and longitudinal monitoring of molecular alterations over time should provide crucial insights into tumour heterogeneity and tumour evolution critical for progression and drug resistance.
The understanding of mechanisms of tumour progression also requires the use of cancer model systems in the laboratory and established cancer cell lines are generally used for this purpose. Such cell lines have often adapted to the laboratory tissue culture environment which changed their characteristics over time. Thus, they frequently behave differently from cells isolated directly from fresh tumour specimens, hindering their use for the identification of drug targets and resistance mechanisms. To circumvent this limitation, we will also use the collected tissues to isolate primary tumour and stromal cells and to maintain them in the laboratory for a limited period of time. This will provide the opportunity to study tumour characteristics in greater detail and will prevent false conclusions which can arise from artifacts which cannot be avoided in long term tissue culture.
Together, these efforts should improve our understanding of tumour evolution over time and reveal some of the mechanisms whih allow tumours to spread through the body and to develop cancer drug resistance. This will be a major improvement over traditional approaches which have most likely failed to identify mechanisms of cancer progression and treatment failure because they relied on single biopsies, missing heterogeneous changes in individual tumours and changes occurring over time (for further information: see Gerlinger et al (NEJM, March 2012) and Yap et al (Sci Transl Med, March 2012).
