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A Systematic Review of the Efficacy of Preclinical Models of Lung Cancer Drugs.

ABSTRACT: Background: Preclinical cell models are the mainstay in the early stages of drug development. We sought to explore the preclinical data that differentiated successful from failed therapeutic agents in lung cancer. Methods: One hundred thirty-four failed lung cancer drugs and twenty seven successful lung cancer drugs were identified. Preclinical data were evaluated. The independent variable for cell model experiments was the half maximal inhibitory concentration (IC50), and for murine model experiments was tumor growth inhibition (TGI). A logistic regression was performed on quartiles (Q) of IC50s and TGIs. Results: We compared odds of approval among drugs defined by IC50 and TGI quartile. Compared to drugs with preclinical cell experiments in highest IC50 quartile (Q4, IC50 345.01-100,000 nM), those in Q3 differed little, but those in the lower two quartiles had better odds of being approved. However, there was no significant monotonic trend identified (P-trend 0.4). For preclinical murine models, TGI values ranged from -0.3119 to 1.0000, with a tendency for approved drugs to demonstrate poorer inhibition than failed drugs. Analyses comparing success of drugs according to TGI quartile produced interval estimates too wide to be statistically meaningful, although all point estimates accord with drugs in Q2-Q4 (TGI 0.5576-0.7600, 0.7601-0.9364, 0.9365-1.0000) having lower odds of success than those in Q1 (-0.3119-0.5575). Conclusion: There does not appear to be a significant linear trend between preclinical success and drug approval, and therefore published preclinical data does not predict success of therapeutics in lung cancer. Newer models with predictive power would be beneficial to drug development efforts.

SUBMITTER: Pan E

PROVIDER: S-EPMC7190806 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Systematic Review of the Efficacy of Preclinical Models of Lung Cancer Drugs.

Pan Elizabeth E Bogumil David D Cortessis Victoria V Yu Sherrie S Nieva Jorge J

Frontiers in oncology 20200423

<b>Background:</b> Preclinical cell models are the mainstay in the early stages of drug development. We sought to explore the preclinical data that differentiated successful from failed therapeutic agents in lung cancer. <b>Methods:</b> One hundred thirty-four failed lung cancer drugs and twenty seven successful lung cancer drugs were identified. Preclinical data were evaluated. The independent variable for cell model experiments was the half maximal inhibitory concentration (IC50), and for muri ...[more]

PMID: 32391273

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Project description:BackgroundAcute respiratory distress syndrome (ARDS) in humans is caused by an unchecked proinflammatory response that results in diffuse and severe lung injury, and it is associated with a mortality rate of 35 to 45%. Mesenchymal stromal cells (MSCs; 'adult stem cells') could represent a promising new therapy for this syndrome, since preclinical evidence suggests that MSCs may ameliorate lung injury. Prior to a human clinical trial, our aim is to conduct a systematic review to compare the efficacy and safety of MSC therapy versus controls in preclinical models of acute lung injury that mimic some aspects of the human ARDS.Methods/designWe will include comparative preclinical studies (randomized and non-randomized) of acute lung injury in which MSCs were administered and outcomes compared to animals given a vehicle control. The primary outcome will be death. Secondary outcomes will include the four key features of preclinical acute lung injury as defined by the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar capillary barrier, lung inflammatory response, and physiological dysfunction) and pathogen clearance for acute lung injury models that are caused by infection. Electronic searches of MEDLINE, Embase, BIOSIS Previews, and Web of Science will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the Cochrane risk of bias tool, and individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.DiscussionThe results of this systematic review will comprehensively summarize the safety and efficacy of MSC therapy in preclinical models of acute lung injury. Our results will help translational scientists and clinical trialists to determine whether sufficient evidence exists to perform a human clinical trial. These results may also guide future acute lung injury preclinical and clinical research.

Project description:Pulmonary arterial hypertension (PAH) is a rare disease (15 cases per million) that is characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary vascular resistance leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies (i.e., therapies involving cells with stem or progenitor-like properties) could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. Preclinical evidence suggests that regenerative cell therapy using endothelial progenitor cells or mesenchymal stem cells may be beneficial in the treatment of PAH. These findings have led to the completion of a small number of human clinical trials, albeit with modest effect compared to animal studies. The objective of this systematic review is to compare the efficacy and safety of regenerative cell therapies in preclinical models of PAH as well as assess study quality to inform future clinical studies.We will include preclinical studies of PAH in which a regenerative cell type was administered and outcomes compared to a disease control. The primary outcome will be pulmonary hemodynamics as assessed by measurement of right ventricular systolic pressure and/or mean pulmonary arterial pressure. Secondary outcomes will include mortality, survival, right ventricular remodeling, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary acceleration time, tricuspid annular systolic excursion, and right ventricular wall thickness. Electronic searches of MEDLINE and EMBASE databases will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool, and individual study reporting will be assessed according to an itemized checklist based on the Animal Research: Reporting of In vivo Experiments (ARRIVE) guidelines.This systematic review will examine the efficacy and safety of regenerative cell therapy in preclinical models of PAH. As well, the literature will be assessed for study quality and risk of bias. The results will guide the design of future clinical trials and preclinical animal studies.CAMARADES ( http://www.dcn.ed.ac.uk/camarades/SyRF/Protocols.htm ).

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A Systematic Review of the Efficacy of Preclinical Models of Lung Cancer Drugs.

Publications

A Systematic Review of the Efficacy of Preclinical Models of Lung Cancer Drugs.

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