Improving Preclinical Cancer Drug Development Models to Avoid Clinical Failure
David A Gewirtz1, Beverly Teicher2, Edward Greenberg3
1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Massey Comprehensive Cancer Center, Richmond, Virginia.
Abstract:
It is well established that the majority of anticancer agents identified and developed through preclinical studies in cell culture and animal models do not prove to be sufficiently effective in the clinic to move into later-stage clinical trials. The simple explanation is that tumor cells in culture or implanted in mice cannot predict what will occur in patients, due in large part to the lack of pharmacokinetics in cell culture and because a mouse is not a miniature human being. Factors such as drug absorption, distribution, metabolism, and excretion (ADME) are likely to be markedly different in mice and humans, and cross-species ADME good laboratory practice toxicology findings are often not fully incorporated into later investigational rodent studies. Furthermore, the frequent use of immune-deficient mice to host human tumors eliminates the critical involvement of the immune system. A colleague once remarked that we can cure virtually all cancers in mice. Although this is certainly hyperbole, it is true that drug efficacy often seems significantly greater in rodent experiments than in humans. This article attempts to highlight and place in perspective many of the issues that limit the utility of preclinical models commonly used for the development of antitumor drugs. We further identify factors that could and should be modified to improve their ultimate translation to the clinic, particularly given current efforts to replace the use of animal models with human cell-based and computer-based assays for drug development.
Insights
Most anti-cancer drugs fail in clinical trials because preclinical models like cell cultures and animal studies do not accurately predict human responses. Improving these models is crucial for effective cancer drug development.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- Preclinical anti-cancer drug development frequently relies on cell cultures and animal models.
- These models often fail to predict clinical efficacy, leading to high attrition rates in drug development.
- Key differences in pharmacokinetics and the absence of immune system involvement in models contribute to this translational gap.
Purpose of the Study:
- To highlight limitations of current preclinical models in anti-cancer drug development.
- To identify factors that hinder the translation of preclinical findings to clinical success.
- To propose modifications for improving preclinical model utility and enhancing clinical translation.
Main Methods:
- Review and analysis of common preclinical models used in anti-cancer drug development.
- Examination of pharmacokinetic (ADME) and immunological differences between preclinical models and human patients.
- Discussion of existing literature and expert opinion on model limitations.
Main Results:
- Preclinical models often overestimate drug efficacy due to simplified biological systems and lack of human-specific factors.
- Pharmacokinetic (drug absorption, distribution, metabolism, excretion) differences between species are significant.
- The use of immune-deficient models excludes the critical role of the immune system in anti-cancer drug response.
Conclusions:
- Current preclinical models have significant limitations that impede the successful translation of anti-cancer drugs to the clinic.
- Modifications to preclinical models, incorporating human-relevant pharmacokinetics and immune system function, are necessary.
- Exploring alternative human cell-based and computer-based assays may improve the predictive power for clinical outcomes.
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