Abstract
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It can be hard to know if a particular cancer drug is working in a particular patient. The drug could be choking off untoward molecular pathways, thwarting the cancer, or it could be gesturing vainly. Knowing which it is doing, sooner rather than later, could allow clinicians to confidently stick with a drug, or switch to another one before the cancer gets out of hand.
To learn whether a cancer drug is actually grappling with a cancer or merely waving it through, scientists at The Institute of Cancer Research (ICR), London, decided to turn to a kind of molecular forensics. They would “dust” for metabolic fingerprints, and instead of squinting through a magnifying glass at the physical evidence, they would watch for peaks coming out of a mass spectrometer.
The results of their investigation appeared in the June issue of Molecular Cancer Therapeutics, in an article entitled, “Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.” As this title indicates, the biomarkers of interest were conveniently located in blood. Less conveniently—or so one might think—the biomarkers that were under suspicion were metabolites, notoriously shifty and light-fingered entities. Metabolites, the building blocks of fats and proteins, vary naturally depending on the time of day or how much food a patient has eaten.
Undaunted, the ICR scientists measured the levels of blood markers in both mice and in human patients. The investigators established that by monitoring a mix of metabolic markers, they could accurately assess how cancers were responding to the targeted drug pictilisib. Pictilisib is designed to specifically target a molecular pathway in cancer cells, called PI3 kinase, which has a key role in cell metabolism and is defective in a range of cancer types.
“Using a mass spectrometry–based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non–tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib,” wrote the researchers. The authors added that almost all of these candidate metabolomics biomarkers were evaluated in a Phase I dose-escalation clinical trial of pictilisib.
“Time- and dose-dependent effects were observed in patients for 22 plasma metabolites,” the authors continued. “The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing.”
Essentially, blood levels of the metabolites began to increase after a single dose of pictilisib, and were seen to drop again when treatment was stopped, suggesting that the effect was directly related to the drug treatment. This finding, the ICR scientists asserted, constituted the first evidence that metabolites, however variable, may be used to determine whether a drug is working.
“We have shown that assessing a patient's metabolites can be a quick and simple way of assessing whether a cancer drug is specifically hitting its intended target in the body,” said Florence Raynaud, Ph.D., a senior researcher at the ICR and the study's author. “Our method was developed specifically for pictilisib but could now be adapted to discover metabolite markers for other cancer treatments.”
Co-author Paul Workman, Ph.D., chief executive of the ICR, emphasized that understanding a drug's mechanism of action was essential to realizing the promise of precision cancer medicine. “By monitoring metabolic signals in the blood, we could make informed decisions about drug development without having to wait years to see the final results of large clinical trials,” he noted. “And our method could eventually be used to monitor patients routinely during the course of treatment, as a quick and easy way of assessing whether a drug is still working, or whether treatment needs to be adapted.”