THE SMART SOLUTION FOR
MOLECULAR TUMOR PROFILING
TUMOR PROFILING TO PREDICT DRUG-SENSITIVE GENOTYPES
Cancer cell lines are selected based on information about the target of a client’s drug. Information about the cell lines is derived from private and multiple publicly available and expertly curated databases including the Wellcome Trust Sanger Institute and the Cell Line Encyclopedia.
The genomes of these cell lines have been characterized for mutations, amplifications, and deletions by sequencing and comparative genome hybridization.
In the graph above, the potency of a drug as a PI3K pathway inhibitor was tested. Selected cell lines were treated with the potential new drug at various concentrations. The affect of the drug can be measured in a number of ways including apoptosis and proliferation. In this example, the affect of the drug was assessed using IC50 in a viability assay.
The mutations that are contained in the cells are aligned with results based on relative sensitivity to the drug. Some mutations may be markers of sensitivity and some may be markers of resistance. Statistical analysis is used to associate mutations with drug activity.
Verification of Pathway Inhibition
Sensitive cell lines are treated with the potential new drug and the cell lysates are then used to determine which protein biomarkers have been affected by treatment with the drug. Cell lysates are spotted onto a surface in arrays. The arrays are then probed with antibodies of known specificity.
The intensity of the spot indicates how much the biomarker was reduced by drug treatment. In the example at right, four sensitive cell lines were treated with a drug; the result was 50-85% decrease in the biomarker reporting on the targeted pathway.
IN VIVO VALIDATION
A drug activity profile defined from in vitro cell line panels is verified in tumor bearing animals. Cell lines sensitive to the drug are injected into mice and optimized for in vivo growth.
Pharmacodynamic modeling is used to determine optimal dosing schedules via several routes of administration. The optimized dosing schedule can be evaluated for efficacy in xenograft studies.
In the figure above, the response of the PD marker in treated mice is dose responsive.
Information gleened from tumor profiling informs the successful design and outcome of in vivo efficacy studies. The optimized cell line model and associated PD assays can be used to support on-going drug development efforts.
We have experience with a variety of mammalian species used for vaccine and drug development. Our studies range from single digit to hundreds of animals.
Our scientists, with over 15 years of GLP experience, provide all aspects of the GLP process from design to regulatory support of your IND, IDE or PMA FDA submission.