Genomics
Concluding remarks X-MAN in vivo G12V G13D Days Control
X-MAN predictions confirmed in patients p.G13D mutation
Cetuximab Days Other K-Ras mutation Months since randomisation Months since randomisation Cetuximab monotherapy No cetuximab therapy Adapted from De Roock W et al, JAMA Oct. 2010
Currently all K-Ras mutant patients excluded from EGFR-targeted therapy X-MAN models harbouring specific K-Ras variants showed not all K-Ras variants impart resistance Retrospective analysis of larger patient cohorts confirm this
Figure 3
colleagues used X-MAN disease models harbouring different K-Ras variants (G12V and G13D) to test whether they are both equally resistant to Cetuximab therapy. In vitro proliferation assays and xenograft- ed tumours, both determined unambiguously that G13D and WT K-Ras containing cells were highly responsive to Cetuximab, whereas G12V containing cells were not (Figure 3). Subsequent sequence analy- sis of tumour samples taken from actual patients treated with Cetuximab confirmed this picture; and thus with follow-up prospective clinical trials, these data may lead to changes in the rules for prescribing EGFR targeted therapies in colon cancer, where cur- rently patients carrying any K-Ras mutation are excluded from therapy. Isogenic models will also form the ideal tool to rationally find rational drug combinations to reverse resistance.
One final area where genetically-defined disease models will help the both later stages of drug development and the prescription of approved drugs is in the development of reliable diagnostic kits and platforms. Armed with isogenic gDNA, which can be mixed in fixed proportions to mimic the heterogenous nature of tumour samples, these will form the perfect precision standards to deter- mine the performance envelope of emerging diag- nostics and as patient-relevant controls for CLIA labs running them.
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Personalised therapies and diagnostics represent the logical direction for providing effective cancer therapy in the future and for the most part, the pharma industry has embraced these ideals; espe- cially since healthcare reimbursers are moving to a system where they pay handsomely for effective medicines and not at all for marginal ones. There is still a limit to how infrequent a target industry will currently tackle, so it is imperative for new functional genomics technologies and genetically- defined disease models to connect the dots. Given the complexity of future clinical trials, pharmaceu- tical companies will probably continue the trend of focusing on late stage development and divesting early-stage research. Here, predictive and patient- relevant disease models will enable the triage of patients into more focused trials with greater cer- tainty of positive outcome and drug approval; and at earlier stages of drug discovery, will enable aca- demia and biotechnology companies to increasing- ly feed validated targets and drug candidates into pharma in a sustainable way. Finally, as a society, it would pay for us to explore ways to incentivise academia and industry to perform research on the wide diversity of rare cancer targets now presented to us, such as targeted translational funding for academia, early pre-approval from successful focused clinical trials and extended patent lifetimes for industry on any new ‘first-in-class’ drugs. These measures would stimulate in an entrepreneurial way the breadth of research and drugs we need; and once available, will likely have larger patient populations than anticipated once they are studied and combined in the right ways.
DDW
Dr Chris Torrance has a bachelor’s degree in Biomedical Technology from Sheffield Polytechnic; a PhD in Biochemistry from East Carolina University (U.S.A) and completed Post-Doctoral training with Professor Bert Vogelstein at the Johns Hopkins University (U.S.A), where he pio- neered the use of X-MAN cancer models in high- throughput screening and drug discovery. Prior to founding Horizon Discovery, Dr Torrance was Head of Oncology and Biology at the UK Biotechnology company Vernalis PLC (LSE: VER), where he was also responsible for progress- ing several novel kinase oncology programmes.
Drug Discovery World Spring 2011
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