Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation
PI3K plays a key role in cellular metabolism and cancer. 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 w...
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American Association for Cancer Research
2019
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| Online-Zugang: | https://demo7.dspace.org/handle/123456789/449 |
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| _version_ | 1860822454883057664 |
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| author | Ang, Joo Ern Pandher, Rupinder Ang, Joo Chew Asad, Yasmin J Henley, Alan T Valenti, Melanie Box, Gary de, Haven Brandon Alexis Baird, Richard Friedman, Lori Derynck, Mika Vanhaesebroeck, Bart Eccles, Suzanne A Kaye, Stan B Workman, Paul de, Bono Johann S Raynaud, Florence I |
| author2 | Antwerp X-ray Analysis, Electrochemistry and Speciation (AXES) |
| author_browse | Ang, Joo Chew Ang, Joo Ern Antwerp X-ray Analysis, Electrochemistry and Speciation (AXES) Asad, Yasmin J Baird, Richard Box, Gary Derynck, Mika Eccles, Suzanne A Friedman, Lori Henley, Alan T Kaye, Stan B Pandher, Rupinder Raynaud, Florence I Valenti, Melanie Vanhaesebroeck, Bart Workman, Paul de, Bono Johann S de, Haven Brandon Alexis |
| author_facet | Antwerp X-ray Analysis, Electrochemistry and Speciation (AXES) Ang, Joo Ern Pandher, Rupinder Ang, Joo Chew Asad, Yasmin J Henley, Alan T Valenti, Melanie Box, Gary de, Haven Brandon Alexis Baird, Richard Friedman, Lori Derynck, Mika Vanhaesebroeck, Bart Eccles, Suzanne A Kaye, Stan B Workman, Paul de, Bono Johann S Raynaud, Florence I |
| author_sort | Ang, Joo Ern |
| collection | DSpace |
| description | PI3K plays a key role in cellular metabolism and cancer. 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 (GDC-0941). 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 changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition. |
| id | oai:localhost:123456789-449 |
| institution | DSPACE.FCHPT |
| language | English |
| publishDate | 2019 |
| publishDateRange | 2019 |
| publishDateSort | 2019 |
| publisher | American Association for Cancer Research |
| publisherStr | American Association for Cancer Research |
| record_format | dspace |
| spelling | oai:localhost:123456789-4492021-04-07T16:30:12Z Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation Ang, Joo Ern Pandher, Rupinder Ang, Joo Chew Asad, Yasmin J Henley, Alan T Valenti, Melanie Box, Gary de, Haven Brandon Alexis Baird, Richard Friedman, Lori Derynck, Mika Vanhaesebroeck, Bart Eccles, Suzanne A Kaye, Stan B Workman, Paul de, Bono Johann S Raynaud, Florence I Antwerp X-ray Analysis, Electrochemistry and Speciation (AXES) PI3K plays a key role in cellular metabolism and cancer. 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 (GDC-0941). 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 changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition. 2019-04-26T08:57:05Z 2019-04-26T08:57:05Z 05/04/16 https://demo7.dspace.org/handle/123456789/449 en American Association for Cancer Research |
| spellingShingle | Ang, Joo Ern Pandher, Rupinder Ang, Joo Chew Asad, Yasmin J Henley, Alan T Valenti, Melanie Box, Gary de, Haven Brandon Alexis Baird, Richard Friedman, Lori Derynck, Mika Vanhaesebroeck, Bart Eccles, Suzanne A Kaye, Stan B Workman, Paul de, Bono Johann S Raynaud, Florence I Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation |
| title | Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation |
| title_full | Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation |
| title_fullStr | Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation |
| title_full_unstemmed | Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation |
| title_short | Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation |
| title_sort | plasma metabolomic changes following pi3k inhibition as pharmacodynamic biomarkers preclinical discovery to phase i trial evaluation |
| url | https://demo7.dspace.org/handle/123456789/449 |
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