A Proposal Regarding Reporting of In Vitro Testing Results

Abstract

The high rate of negative clinical trials and failed drug development programs calls into question the utility of preclinical testing as currently practiced. An important issue for the in vitro testing of agents that have advanced into the clinic is the use of clinically irrelevant concentrations in reports making claims for anticancer activity, as illustrated by publications for sorafenib, vorinostat, and metformin. For sorafenib, high protein binding leads to a dichotomy between concentrations active in the 10% serum conditions commonly used for in vitro testing and concentrations active in plasma. Failure to recognize this distinction leads to inappropriate claims of activity for sorafenib based on the micromolar concentrations commonly used for in vitro testing in low serum conditions. For vorinostat and metformin, results using in vitro concentrations higher than those achievable in patients are reported despite the availability of publications describing human pharmacokinetic data for each agent. We encourage journal editors and reviewers to pay greater attention to clinically relevant concentrations when considering reports that include in vitro testing of agents for which human pharmacokinetic data are available. Steps taken to more carefully scrutinize activity claims based on in vitro results can help direct researchers away from clinically irrelevant lines of research and toward lines of research that are more likely to lead to positive clinical trials and to improved treatments for cancer patients.

The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

“…The combination appeared more active in ABC-DLBCL cell lines, maybe due the common targeting of the IL10 and STAT3 pathway by both OTX015 and rituximab (48). OTX015 presented synergism with the demethylating agent decitabine and the HDACi vorinostat at concentrations pharmacologically achievable in clinical use (49,50), in accordance with the similarities here observed at the level of gene expression signatures, and also with published data obtained with other BET bromodomain inhibitors (11). HDACs of both classes I and II were associated with a lower sensitivity to OTX015 as single agent and, indeed the synergism appeared stronger with the class I and IIa/b HDACi vorinostat than that seen with the class I HDACi romidepsin suggesting that the synergism might be class dependent.…”

“…To identify genes and pathways that might predict sensitivity to OTX015 in DLBCL we integrated the sensitivity data with the baseline gene expression profile in 14 cell lines with an IC 50 lower than 500 nmol/L and eight with a higher IC 50 .…”

The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models

“…This could potentially reflect enhanced CNS penetration by brigatinib or the greater potency of brigatinib over crizotinib making it less susceptible to pharmacologic failure in mice. When evaluating the in vitro potency of TKIs and the potential therapeutic implications, it is critical to consider these data in the context of TKI levels achieved in patients at the recommended dose (25). Possibly due to its high selectivity for ALK (and ROS1), two kinases with limited expression in adults (26), brigatinib can achieve levels of exposure in patients that substantially exceed those required to inhibit native ALK.…”

Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP

“…The drug concentrations used in this study were carefully selected to perform a clinically relevant in vitro study (25). Synergistic cytotoxic effects were induced by the combination treatment at clinically achievable concentrations, which are below the peak plasma concentrations of recommended phase 2 doses for each drug (5.33–6.61 µ M and 50 nM for ABT-263 and BMN 673, respectively) (15,26,27).…”