HOME HELP FEEDBACK HOW TO CITE ABSTRACTS ARCHIVE CME INFORMATION SEARCH Cancer Research Clinical Cancer Research Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics Molecular Cancer Research Cancer Prevention Research Cancer Prevention Journals Portal Cancer Reviews Online Annual Meeting Education Book Meeting Abstracts Online		QUICK SEARCH:   [advanced] Author: Keyword(s):

This Article Services Similar articles in this journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Maitland, M. L. Articles by Ratain, M. J. Search for Related Content PubMed Articles by Maitland, M. L. Articles by Ratain, M. J.

Targeted Therapies and Clinical Translational Research: Other Therapies

Stepwise development of biomarkers for angiogenic activity with standardized assays for circulating molecules in human subjects

Dept. Medicine, Sect. Hem/Onc, Chicago, IL, University of Chicago, Dept. Health Studies, Chicago, IL, Clinical Pharmacology Core Laboratory, Chicago, IL, Dept. Health Studies, Chicago, IL, Dept. Medicine, Sect. Hem/Onc, Cancer Research Center, Chicago, IL

Abstract

B84

Numerous molecules are necessary for tumor angiogenesis and standardized assays for determining the concentrations of such molecules in body fluids are readily available. It is unclear which assays, upon which fluid samples, will be useful biomarkers to guide anticancer therapy. In this study we: 1) selected angiopoietin-2 (Ang2) and soluble vascular endothelial growth factor receptor-2 (VEGFR2) for further investigation based on parameters of assay performance in population samples, 2) estimated the intraindividual and interindividual variability in measurements on serially collected serum and plasma samples from 6 healthy adult subjects, and 3) applied these findings to the pilot analysis of these same markers in a group of advanced cancer patients receiving treatment with the c-Raf/VEGFR2/VEGFR3/PDGFRß kinase inhibitor sorafenib. Ang2 and VEGFR2 shared properties of primary synthesis by endothelial cells and ELISAs (R Systems, Minneapolis, MN) detecting a broad population distribution with no sample below the limits of detection. The six healthy subjects provided 13 concurrent serum and plasma samples each over the course of 14-24 days Variance component analysis revealed 86% of plasma Ang2 and 91% of plasma VEGFR2 variability to be interindividual, with sex and a standardized exercise session having no obvious measurable effect. (For serum samples, interindividual variation accounted for 89% and 87% of the total variance for Ang2 and VEGFR2, respectively.) For Ang2, serum and plasma samples yielded nearly identical results while VEGFR2 serum samples had slightly greater intraindividual variability than plasma samples. Therefore single time-point plasma samples were collected from 15 advanced solid tumor patients, before, and approximately 10 and 40 days after commencing treatment with the orally available kinase inhibitor sorafenib. Using a repeated measures linear model of Ang2 and VEGFR2 concentrations, a univariate test of the time on sorafenib effect was statistically significant (Greenhouse-Geisser p value= 0.046 and <0.0001 respectively). But maximum mean change for Ang2 was 563pg/ml (within the intraindividual variability for healthy subjects) while for sVEGFR2 it was 1658pg/ml (greater than the measured intraindividual variability for healthy subjects). This work demonstrates a potentially useful human subject-oriented approach to therapy-biomarker development and will guide the future investigation of the biology and clinical relevance of Ang2 and VEGFR2 concentrations during anticancer therapy.