Related Experiment Video
Updated: Oct 10, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Comparative Study on the Efficacy and Exposure of Molecular Target Agents in Non-small Cell Lung Cancer PDX Models
Hitomi Jo1,2, Shigehiro Yagishita1, Yoshiharu Hayashi1,3,4
1Division of Molecular Pharmacology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Abstract:
Patient-derived xenografts (PDX) can adequately reflect clinical drug efficacy. However, the methods for evaluating drug efficacy are not fully established. We selected five non-small cell lung cancer (NSCLC) PDXs with genetic alterations from established PDXs and the corresponding molecular targeted therapy was administered orally for 21 consecutive days. Genetic analysis, measurement of drug concentrations in blood and tumors using LC/MS-MS, and analysis of drug distribution in tumors using matrix-assisted laser desorption/ionization mass spectrometry were performed. Fifteen (20%) PDXs were established using samples collected from 76 patients with NSCLC with genetic alterations. The genetic alterations observed in original patients were largely maintained in PDXs. We compared the drug efficacy in original patients and PDX models; the efficacies against certain PDXs correlated with the clinical effects, while those against the others did not. We determined blood and intratumor concentrations in the PDX model, but both concentrations were low, and no evident correlation with the drug efficacy could be observed. The intratumoral spatial distribution of the drugs was both homogeneous and heterogeneous for each drug, and the distribution was independent of the expression of the target protein. The evaluation of drug efficacy in PDXs enabled partial reproduction of the therapeutic effect in original patients. A more detailed analysis of systemic and intratumoral pharmacokinetics may help clarify the mode of action of drugs. Further development of evaluation methods and indices to improve the prediction accuracy of clinical efficacy is warranted.
Insights
Patient-derived xenografts (PDXs) partially predict non-small cell lung cancer (NSCLC) drug efficacy. Pharmacokinetic analysis in PDX models is crucial for improving clinical prediction accuracy.
Area of Science:
- Oncology
- Pharmacology
- Translational Research
Background:
- Patient-derived xenografts (PDXs) are valuable tools for assessing cancer drug efficacy.
- Established methods for evaluating drug efficacy in PDXs require further refinement.
Purpose of the Study:
- To evaluate the correlation between drug efficacy in non-small cell lung cancer (NSCLC) PDXs and clinical outcomes.
- To investigate the pharmacokinetic and pharmacodynamic properties of targeted therapies in NSCLC PDXs.
Main Methods:
- Five NSCLC PDXs with genetic alterations were selected for molecular targeted therapy administration.
- Genetic analysis, LC/MS-MS for drug concentrations, and MALDI-MS for drug distribution were performed.
- Drug efficacy in PDXs was compared with clinical effects in original patients.
Main Results:
- NSCLC PDXs largely maintained the genetic alterations of the original tumors.
- Drug efficacy showed correlation with clinical effects in some PDXs but not others.
- Low blood and intratumoral drug concentrations were observed, with no clear correlation to efficacy.
Conclusions:
- PDX models partially replicate therapeutic effects observed in NSCLC patients.
- Further analysis of systemic and intratumoral pharmacokinetics is needed to understand drug action.
- Development of improved evaluation methods is warranted to enhance clinical efficacy prediction.
