Horizon Discovery Ltd.'s X-MAN Cell-models Predict that a Subset of KRAS Mutated Cancers Respond to EGFR Therapy
Specifically, the study found that patients carrying a particular and relatively common (20% of mutant KRAS cases) form of mutant KRAS (the G13D variant) are not resistant to Erbitux therapy, as previously thought. These findings therefore suggest that further analysis of specific mutant KRAS variants in prospective clinical trials are required to study the impact of specific mutant KRAS variants on Erbitux therapy.
This new study follows on from previous studies from Professor Bardelli and Tejpar published in the Journal of Cancer Research (March 2007 and February 2009) and the Journal of Clinical Oncology (October 2008), which first made the link between KRAS mutations (as well as other mutant biomarkers; BRAF and PI3K) and resistance to novel EGFR targeting colorectal cancer drugs; Erbitux and Vectibix, in up to 65% of colon cancer patients when tumour samples and response data were analysed retrospectively. These data were subsequently confirmed in prospective trials and it is now mandatory to test colorectal cancer patients for their KRAS status before they are prescribed these therapies; if a patient carries any mutational variant of KRAS (G12A, C, D, R, S, V or G13D) they are excluded from Erbitux therapy. However, the findings of this new study, which used human cell lines harbouring G13D or G12V mutations and DNA-sequence analysis of patient tumours, defined that while G12V mutations (28 % of KRAS mutated cases) do impart resistance to Erbitux therapy, G13D mutations (20% of KRAS mutated cases) do not.
The genetically defined and patient-relevant X-MAN human cell models used in this study were created by Professor Bardelli using Horizon’s proprietary virally-mediated gene-engineering technology calledGENESIS™, which allows researchers to precisely engineer any DNA-variation into a human cell. The key feature is that these DNA-variations (in this case 7 different mutant KRAS variations) are introduced into endogenous genes, just as they occur in patients. These disease models therefore allow key questions on drug effectiveness to be addressed prior to testing in clinical trials; and informing retrospective analysis of clinical trials where possible.
Commenting on the study, Dr Chris Torrance, CEO of Horizon Discovery, said: “This study demonstrates the potential of Horizon’s genetically-defined X-MAN human disease models for predicting drug responses in specific patient cohorts, based on their underlying disease genetics. Specifically in this case, X-MAN models can accurately predict KRAS mediated resistance to anti-EGFR drugs and potentially other targeted drugs that have not yet been tested for the impact of KRAS mutations. Moreover, gDNA derived from these X-MAN models will form a crucial reference material for current and future companion diagnostic tests. This is an area of great need as the role of clinical diagnostics becomes the norm for directing drug treatments, saving significant time and costs for drug developers and healthcare providers; and better outcomes for the patient. ”
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ABOUT HORIZON DISCOVERY www.horizondiscovery.com
Horizon Discovery is a leading provider of research tools to support the development of personalized medicines. The Company’s proprietary virally-mediated gene-engineering technology, GENESIS™, enables any endogenous gene in a human cell-line to be altered quickly, reliably and without introducing unwanted and confounding genotypes and/or phenotypes. Using GENESIS, Horizon Discovery has developed X-MAN™ (Gene-X; Mutant AndNormal) cell models, which are the world’s first source of genetically-defined and patient-relevant human cell lines.
The Company’s broad panel of over 250 different X-MAN cell lines, which have been referred to as “patients-in-a-test-tube,” accurately model the disease-causing mutations in cancer patients. The X-MAN cell lines are being used by academic and industry leaders to identify the effect of individual mutations on drug activity, patient responsiveness and resistance, and to successfully predict which patient sub-groups will respond to currently-available and future drug treatments. This supports the design of shorter, more focused clinical trials, making it possible to identify the ‘right drugs’ for the ‘right patients’ based upon the unique genetic mutations that define their disease.
Founded in 2007 by Dr Chris Torrance and Professor Alberto Bardelli, and with headquarters in Cambridge, UK, the company builds on a long heritage in gene-engineering, cancer research and translational medicine, and draws on intellectual property and know-how from the University of Washington, the Johns Hopkins University, the University of Maryland, the University of Minnesota and the Department of Oncological Sciences at the University of Torino Medical School. Over 150 scientific papers relating to the use of X-MAN cell line pairs generated using GENESIS have been published, and the technology has won numerous awards including; Medical Futures Innovation Award for Cancer (2008), UK iaward of the Year (2009), and East of England Killer Technology (2010).