A Strategy for Early Detection of Response to Chemotherapy Drugs Based on Treatment-Related Changes in the Metabolome Publisher Pubmed



Amin S¹ ; Rattner J¹ ; Keramati MR^{1, 2} ; Farshidfar F¹ ; Mcnamara MG³ ; Knox JJ⁴ ; Kopciuk K⁵ ; Vogel HJ⁶ ; Bathe OF^{1, 7, 8}
Source: PLoS ONE Published:2019

Abstract

We describe a biomarker-based approach to delivering chemotherapy that entails monitoring treatment changes in the circulating metabolome that reflect efficacy. In-vitro, multiple tumor cell lines were exposed to numerous chemotherapeutics. Supernatants were collected at baseline and 72 hours post treatment. MTT assays were used to quantify growth inhibition. Clinical samples were derived from a phase II clinical trial of second-line axitinib in patients with advanced hepatocellular carcinoma. Sera were collected at baseline and 2–4 weeks after treatment initiation. Response to therapy was estimated by CT scan at 8 weeks. Samples were analyzed by gas chromatography-mass spectrometry to identify metabolomic changes associated with response. In vitro, we found drug-specific and generalizable patterns of change in the extracellular metabolome accompany growth inhibition. A cell death signature was also identified. This approach was also applied to clinical samples. While the in vitro signatures were detectable in vivo, a more robust signal was identified clinically that appeared within 4 weeks of administering drug that distinguished individuals with a treatment response. These changes were extinguished as tumor growth resumed. Serial monitoring of the metabolome during chemotherapy is a means to follow treatment efficacy and emergence of resistance, informing the oncologist whether to modify treatment. © 2019 Amin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.