Image: The AbsoluteIDQ p180 Kit for Metabolic Phenotyping (Photo courtesy of Biocrates Life Sciences).
As a minimally invasive assessment, plasma metabolomic analysis has the potential to complement direct tumoral measurements and, particularly where cancer biopsies are unavailable, and can report on the integrated output of multiple systems including sites of disease.
Testing for metabolic changes in the blood could indicate whether a cancer drug is working as designed, and by measuring how cancer treatment affects the levels of metabolites, the building blocks of fats and proteins, those levels can be used to assess whether the drug is hitting its intended target.
Scientists at the Institute of Cancer Research (London, UK) and a team of international collaborators measured the levels of 180 blood markers in 41 patients with advanced cancers in a phase I clinical trial. The drug pictilisib is designed to specifically target a molecular pathway in cancer cells, called phosphatidylinositide 3-kinase (PI3K), which has key a role in cell metabolism and is defective in a range of cancer types. As cancers with PI3K defects grow, they can cause a decrease in the levels of metabolites in the bloodstream.
Non-targeted liquid chromatography–mass spectrometry (LC-MS) metabolomics was initially used in the preclinical screen as significant changes in plasma metabolites were identified. To follow-up and confirm these preliminary findings, the scientists carried out targeted, quantitative metabolomic analysis by electrospray ionization tandem MS using the AbsoluteIDQ p180 Kit (Biocrates Life Sciences AG, Innsbruck, Austria). Samples were anonymized and analyses were carried out on an Acquity H-class UPLC coupled to Xevo TQ-S triple-quadrupole MS/MS System (Waters Corporation, Milford, MA, USA).
The authors found in a mouse model that the blood levels of 26 different metabolites, which were low prior to therapy, had risen considerably following treatment with pictilisib. Their findings indicated that the drug was hitting its target, and reversing the effects of the cancer on mouse metabolites. Similarly, in humans they found that almost all of the metabolites, 22 out of the initial 26, once again rose in response to pictilisib treatment, as seen in the mice. 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.
Florence J. Raynaud, PhD, a senior author of the study, said, “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. Our study is an important step in the development of new precision cancer therapies, and is the first to show that blood metabolites have real potential to monitor the effects of novel agents. Our method was developed specifically for pictilisib but could now be adapted to discover metabolite markers for other cancer treatments.” The study was published on April 5, 2016, in the journal Molecular Cancer Therapeutics.
Institute of Cancer Research
Biocrates Life Sciences