Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin

Roy S. Herbst, Nizar A. Mullani, Darren W. Davis, Kenneth R. Hess, David McConkey, Chusilp Charnsangavej, Michael S. O'Reilly, Hyung Woo Kim, Cheryl Baker, Jennifer Roach, Lee M. Ellis, Asif Rashid, James Pluda, Corazon Bucana, Timothy L. Madden, Hai T. Tran, James L. Abbruzzese

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Abstract

Purpose: Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy. Patients and Methods: Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [15O]H2O) and metabolism (with [18F]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis. Results: Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P = .027) and endothelial cell apoptosis (P = .027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis. Conclusion: These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required.

Original languageEnglish (US)
Pages (from-to)3804-3814
Number of pages11
JournalJournal of Clinical Oncology
Volume20
Issue number18
DOIs
Publication statusPublished - Sep 15 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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