Drug Resistance
The growing need for genetically-defined models in the field of cancer has been driven by Professor Bardelli’s studies, published in the Journal of Cancer Research (March 2007) and the Journal of Clinical Oncology (October 2008).
These studies retrospectively analyzed tissue samples from the clinical trials performed for the novel ‘EGFR’ targeting colorectal cancer drugs; Erbitux and Vectibix and found that the majority of patients that carry a secondary mutant gene (KRAS and BRAF) are resistant to these drugs (in a combined total of 52% of patients trialed). These data were subsequently confirmed in prospective trials performed by the pharmaceutical companies developing these drugs; and the European Medicines Agency (EMEA) and the Food and Drug Administration (FDA) have now mandated the compulsory testing of all colon cancer patients for their mutant KRAS status before Erbitux and Vectibix can be prescribed. The American Society of Clinical Oncologists (ASCO) had determined that KRAS testing has saved the global healthcare industry $750 million in mis-prescription of these drugs.
A follow-on study, published by Professor Alberto Bardelli (University of Torino) and Sabine Tejpar (University of Leuven) in the Journal of The American Medical Association (October 2010) used X-MAN cell lines (see figure below) to drive a detailed retrospective analysis of colon cancer patients who are prescribed, or excluded from Erbitux therapy based on the presence or absence of ‘mutant KRAS’.
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. The in vitro, in vivo and clinical sample data correlated closely therefore suggesting 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.
The above findings/rulings have limited the market size, profitability and patient efficacy of these drugs at a time when hundreds of millions of dollars have been spent on their development. However, if it can be determined that a rational combination of drugs to use in genetically characterised resistant patients, the market size for your drug can soon expand dramatically.
Patient-relevant X-MAN cancer cell-models can predict such genetic-based clinical outcomes for single and combinatorial treatment regimens; guiding focused project development; clinical trial design and the recruitment and marketing/co-marketing of more effective therapeutic regimens.
X-MAN Discovery 2 (double mutation knock-in) cell-lines model the precise effects of secondary mutations on primary patient genotypes known to respond to a clinical EGFR active drug (Gefitinib). See below data/graph.
Horizon Offering
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Horizon Discovery has a wide range of isogenic models available for immediate licensing or purchasing (learn more) and; can also develop custom isogenic models (learn more) or screen drug candidates against your specific gene target (learn more). |
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Additional data-sets are available for each application and can be shared under confidential disclosure agreement. Please contact us for more information. |
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References
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