Related Experiment Videos
Extending principles learned in model systems to clinical trials design
P J Houghton1, C F Stewart, J Thompson
1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Abstract:
Clinical results with irinotecan (CPT-11 [Camptosar]) and other camptothecin derivatives in various cancers, although encouraging, have fallen short of the expectations predicted by preclinical models. One proposed explanation for this is that preclinical xenograft models do not predict for the sensitivity of human cancer. In this article, we describe the results of several studies suggesting that this explanation is incorrect. Instead, our results indicate that the discrepancy between clinical response rates and findings in preclinical models may be due to a failure to incorporate the principles learned from preclinical studies into the design of clinical trials. Our analysis suggests that if differences in host tolerance are taken into account, the xenograft models are quite accurate predictors of clinical response. Moreover, application of the principles derived from preclinical models to the design of clinical trials may significantly enhance clinical response rates. Thus, the camptothecin analogs provide a paradigm for better integrated, pharmacokinetically driven, preclinical and clinical development of new drugs.
Insights
Preclinical cancer models accurately predict clinical response to irinotecan (CPT-11) and camptothecin analogs when host tolerance is considered in clinical trial design. Optimizing trial design enhances drug efficacy.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- Clinical outcomes with irinotecan (CPT-11) and other camptothecin derivatives in cancer treatment have not met preclinical predictions.
- A common hypothesis suggests preclinical xenograft models fail to predict human cancer sensitivity.
Purpose of the Study:
- To investigate the discrepancy between preclinical findings and clinical outcomes for camptothecin derivatives.
- To re-evaluate the predictive accuracy of preclinical xenograft models in cancer drug development.
Main Methods:
- Analysis of existing preclinical and clinical data for irinotecan and related compounds.
- Comparative assessment of xenograft model predictions versus actual clinical response rates.
- Evaluation of the impact of host tolerance factors on drug efficacy.
Main Results:
- Preclinical xenograft models are accurate predictors of clinical response when host tolerance differences are incorporated into clinical trial design.
- The discrepancy between preclinical and clinical results is attributed to suboptimal clinical trial design, not model inaccuracy.
- Adjusting clinical trial parameters based on preclinical data can significantly improve response rates.
Conclusions:
- Camptothecin analogs demonstrate the potential for integrated, pharmacokinetically driven preclinical and clinical drug development.
- Optimizing clinical trial design based on preclinical principles is crucial for enhancing cancer therapeutic efficacy.
- Future drug development should prioritize the translation of preclinical insights into robust clinical trial strategies.