Molecular Diagnostics
and gastric cancers, and the KRAS mutation test, which is on the label of the anti-EGFR therapeutic antibody cetuximab (Erbitux™) for advanced col- orectal cancer.
Both of these are examples of a rational approach to the development of a predictive. However, not all current predictives are the prod- uct of such an approach; many have been discov- ered after the fact, as a result of the enormous power of modern genetic analysis techniques (Table 1). Interestingly, molecular (DNA/RNA- based) technology was adopted by the infectious diseases drug development sector long before the oncology sector picked up on it, and to that extent the oncology field has been playing catch-up. Another important driver in the rush to discover new predictive biomarkers has been the (ethically commendable) desire to extract as much informa- tion as possible from the valuable patient samples that arise as part of clinical investigation or from surgical resection. Hospital pathology departments have accumulated many decades of archival mate- rial preserved with formalin. Until recently this material was only of utility for standard histopathology tests, which included immunohisto- chemistry and, more recently, fluorescence in situ hybridisation (FISH). However, the development of techniques for extracting and analysing DNA, RNA and proteins from tissue originally removed from a patient several decades ago has produced a wealth of new information about the relationship between the genetic make-up of an individual, their disease prognosis and likely response to drugs (pharmacogenomics). Therefore, with the benefit of retrospective analysis of patients whose disease was diagnosed and treated in the past, we can now make more informed and accurate prediction about the prognosis and likely response to treat- ment of a newly-diagnosed patient.
While the costs of such global analysis of a
patient’s DNA are currently too great for the resources of the UK’s National Health Service, the global landscape is changing rapidly. In the US, the Dana-Farber and Memorial Sloan Kettering Cancer Centres are introducing routine profiling of a comprehensive set of 1,200 somatic mutations and key polymorphisms in 150 cancer-associated genes using mass-spectrometry. Cancer Research UK, in collaboration with Pfizer and AstraZeneca, has initiated a ‘Stratified Medicine Programme’ that will evaluate the feasibility of prospectively analysing key sets of somatic mutations and poly- morphisms with known predictive value in approximately 9,000 patients over two years. In parallel, the UK Technology Strategy Board is
Drug Discovery World Spring 2011
offering competitive awards to academic and com- mercial organisations to collaborate on the devel- opment of new technology for ‘tumour profiling’. It is clear that NGS is likely to play a significant part in these developments, based on its unparal- leled ability to scan the entire genome in an unbi- ased manner, at the same time looking at each nucleotide multiple times.
The future is imaging
For all the power and beauty of modern molecular technology, the future of diagnostics (diagnostics, prognostics and predictives) must lay in imaging. Imaging will be used to diagnose the presence of a tumour, to characterise that tumour and to moni- tor its response to treatment. In terms of anatomi- cal information computerised tomography (CT) and magnetic resonance imaging (MRI) are the most accurate imaging modalities. However; these techniques often lack the ability to distinguish between tumour and normal tissues. ‘Molecular’ imaging using positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) allows clearer visualisation of tumours and their metabolic activity, based upon their enhanced glu- cose metabolism. Other PET tracers that can be used to track characteristics such as proliferation, hypoxia and expression of key receptors such as HER2 and EGFR, are being increasingly used in evaluation of tumours, and may have predictive power for response to treatment. Recent studies have suggested the added benefits of integrated PET-CT, which will combine functional and anatomical imaging.
Final thoughts In a recent article4 Robert Landreth discussed the question of why pharmas are struggling to cure can- cer, despite pouring resources into the search for new treatments. Some drugs that make it through to licensing do show benefit, but more often than not for a small proportion, a subset of patients with a particular type of cancer. In the case of many so- called targeted drugs there is also now a ‘compan- ion diagnostic’, which more often than not assists in excluding patients from treatment. As an eminent oncologist said to me the other day: “The problem is that with all these tests, soon I’ll have nothing I can offer my patients.” There is a hard truth to this slightly cynical remark. Garth Anderson of Roswell Park Cancer Institute being interviewed in the same article points out that with new technology we will reveal more and more mutations and other genetic changes. Furthermore this is a dynamic situation; changes are occurring all the time. Many of these
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