Originally published as JCO Early Release 10.1200/JCO.2002.05.102 on August 12 2002

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Herbst, R. S. Articles by Abbruzzese, J. L. Search for Related Content PubMed PubMed Citation Articles by Herbst, R. S. Articles by Abbruzzese, J. L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cancer Cancer Chemotherapy Social Bookmarking                            What's this?

Development of Biologic Markers of Response and Assessment of Antiangiogenic Activity in a Clinical Trial of Human Recombinant Endostatin

From the Departments of Thoracic and Head and Neck Medical Oncology, Cancer Biology, Biostatistics, Diagnostic Radiology, Radiation Oncology, Surgical Oncology, Pathology, Pharmaceutical Sciences, and Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, and The University of Texas Medical School, Houston, TX; and National Cancer Institute, Bethesda, MD.

Address reprint requests to Roy S. Herbst, MD, PhD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX; email: rherbst{at}mdanderson.org

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.

N.A.M., D.W.D., and K.R.H. contributed equally to this work.

This article was published ahead of print at www.jco.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				K. B. Contractor and E. O. Aboagye Monitoring Predominantly Cytostatic Treatment Response with 18F-FDG PET J. Nucl. Med., May 1, 2009; 50(Suppl_1): 97S - 105S. [Abstract] [Full Text] [PDF]

				A. J. de Langen, M. Lubberink, R. Boellaard, M. D. Spreeuwenberg, E. F. Smit, O. S. Hoekstra, and A. A. Lammertsma Reproducibility of Tumor Perfusion Measurements Using 15O-Labeled Water and PET J. Nucl. Med., November 1, 2008; 49(11): 1763 - 1768. [Abstract] [Full Text] [PDF]

				C. de Bazelaire, D. C. Alsop, D. George, I. Pedrosa, Y. Wang, M. D. Michaelson, and N. M. Rofsky Magnetic Resonance Imaging-Measured Blood Flow Change after Antiangiogenic Therapy with PTK787/ZK 222584 Correlates with Clinical Outcome in Metastatic Renal Cell Carcinoma Clin. Cancer Res., September 1, 2008; 14(17): 5548 - 5554. [Abstract] [Full Text] [PDF]

				A. J. de Langen, V. E. M. van den Boogaart, J. T. Marcus, and M. Lubberink Use of H215O-PET and DCE-MRI to Measure Tumor Blood Flow Oncologist, June 1, 2008; 13(6): 631 - 644. [Abstract] [Full Text] [PDF]

				N. A. Mullani, R. S. Herbst, R. G. O'Neil, K. L. Gould, B. J. Barron, and J. L. Abbruzzese Tumor Blood Flow Measured by PET Dynamic Imaging of First-Pass 18F-FDG Uptake: A Comparison with 15O-Labeled Water-Measured Blood Flow J. Nucl. Med., April 1, 2008; 49(4): 517 - 523. [Abstract] [Full Text] [PDF]

				P. Beaudry, M. Nilsson, M. Rioth, D. Prox, D. Poon, L. Xu, P. Zweidler-Mckay, A. Ryan, J. Folkman, S. Ryeom, et al. Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium Mol. Cancer Ther., February 1, 2008; 7(2): 418 - 424. [Abstract] [Full Text] [PDF]

				D. S. Boss, R. V. Olmos, M. Sinaasappel, J. H. Beijnen, and J. H. M. Schellens Application of PET/CT in the Development of Novel Anticancer Drugs Oncologist, January 1, 2008; 13(1): 25 - 38. [Abstract] [Full Text] [PDF]

				G. Bix, R. Castello, M. Burrows, J. J. Zoeller, M. Weech, R. A. Iozzo, C. Cardi, M. L. Thakur, C. A. Barker, K. Camphausen, et al. Endorepellin In Vivo: Targeting the Tumor Vasculature and Retarding Cancer Growth and Metabolism. J Natl Cancer Inst, November 15, 2006; 98(22): 1634 - 1646. [Abstract] [Full Text] [PDF]

				W. A. Weber Positron Emission Tomography As an Imaging Biomarker J. Clin. Oncol., July 10, 2006; 24(20): 3282 - 3292. [Abstract] [Full Text] [PDF]

				M. Atri New Technologies and Directed Agents for Applications of Cancer Imaging J. Clin. Oncol., July 10, 2006; 24(20): 3299 - 3308. [Abstract] [Full Text] [PDF]

				K. Schmidt, J. Hoffend, A. Altmann, L. G. Strauss, A. Dimitrakopoulou-Strauss, B. Engelhardt, D. Koczan, J. Peter, T. J. Dengler, W. Mier, et al. Angiostatin Overexpression in Morris Hepatoma Results in Decreased Tumor Growth but Increased Perfusion and Vascularization J. Nucl. Med., March 1, 2006; 47(3): 543 - 551. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, J. S. Carew, M. S. Pino, R. A. Highshaw, K. Dunner Jr., P. Huang, J. L. Abbruzzese, and D. J. McConkey Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis Cancer Res., December 15, 2005; 65(24): 11658 - 11666. [Abstract] [Full Text] [PDF]

				A. H. G. Hansma, H. J. Broxterman, I. van der Horst, Y. Yuana, E. Boven, G. Giaccone, H. M. Pinedo, and K. Hoekman Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections: a phase I and pharmacokinetic study in patients with advanced cancer Ann. Onc., October 1, 2005; 16(10): 1695 - 1701. [Abstract] [Full Text] [PDF]

				G. Liu, H. S. Rugo, G. Wilding, T. M. McShane, J. L. Evelhoch, C. Ng, E. Jackson, F. Kelcz, B. M. Yeh, F. T. Lee Jr, et al. Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study J. Clin. Oncol., August 20, 2005; 23(24): 5464 - 5473. [Abstract] [Full Text] [PDF]

				G. Li, L. Tian, J.-m. Hou, Z.-y. Ding, Q.-m. He, P. Feng, Y.-j. Wen, F. Xiao, B. Yao, R. Zhang, et al. Improved Therapeutic Effectiveness by Combining Recombinant CXC Chemokine Ligand 10 with Cisplatin in Solid Tumors Clin. Cancer Res., June 1, 2005; 11(11): 4217 - 4224. [Abstract] [Full Text] [PDF]

				P. Beaudry, J. Force, G. N. Naumov, A. Wang, C. H. Baker, A. Ryan, S. Soker, B. E. Johnson, J. Folkman, and J. V. Heymach Differential Effects of Vascular Endothelial Growth Factor Receptor-2 Inhibitor ZD6474 on Circulating Endothelial Progenitors and Mature Circulating Endothelial Cells: Implications for Use as a Surrogate Marker of Antiangiogenic Activity Clin. Cancer Res., May 1, 2005; 11(9): 3514 - 3522. [Abstract] [Full Text] [PDF]

				K. Schmidt, J. Hoffend, A. Altmann, L. G. Strauss, A. Dimitrakopoulou-Strauss, B. Engelhardt, D. Koczan, J. Peter, S. Vorwald, H. Eskerski, et al. Transfer of the sFLT-1 Gene in Morris Hepatoma Results in Decreased Growth and Perfusion and Induction of Genes Associated with Stress Response Clin. Cancer Res., March 15, 2005; 11(6): 2132 - 2140. [Abstract] [Full Text] [PDF]

				G. Gasparini, R. Longo, M. Fanelli, and B. A. Teicher Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions J. Clin. Oncol., February 20, 2005; 23(6): 1295 - 1311. [Abstract] [Full Text] [PDF]

				S. Rehman and G. C. Jayson Molecular Imaging of Antiangiogenic Agents Oncologist, February 1, 2005; 10(2): 92 - 103. [Abstract] [Full Text] [PDF]

				D. W. Davis, R. Takamori, C. P. Raut, H. Q. Xiong, R. S. Herbst, W. M. Stadler, J. V. Heymach, G. D. Demetri, A. Rashid, Y. Shen, et al. Pharmacodynamic Analysis of Target Inhibition and Endothelial Cell Death in Tumors Treated with the Vascular Endothelial Growth Factor Receptor Antagonists SU5416 or SU6668 Clin. Cancer Res., January 15, 2005; 11(2): 678 - 689. [Abstract] [Full Text] [PDF]

				R. K. Jain Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy Science, January 7, 2005; 307(5706): 58 - 62. [Abstract] [Full Text] [PDF]

				J. V. Heymach, J. Desai, J. Manola, D. W. Davis, D. J. McConkey, D. Harmon, D. P. Ryan, G. Goss, T. Quigley, A. D. Van den Abbeele, et al. Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas Clin. Cancer Res., September 1, 2004; 10(17): 5732 - 5740. [Abstract] [Full Text] [PDF]

				D. W. Davis, K. Inoue, C. P. N. Dinney, D. J. Hicklin, J. L. Abbruzzese, and D. J. McConkey Regional Effects of an Antivascular Endothelial Growth Factor Receptor Monoclonal Antibody on Receptor Phosphorylation and Apoptosis in Human 253J B-V Bladder Cancer Xenografts Cancer Res., July 1, 2004; 64(13): 4601 - 4610. [Abstract] [Full Text] [PDF]

				T. Inai, M. Mancuso, H. Hashizume, F. Baffert, A. Haskell, P. Baluk, D. D. Hu-Lowe, D. R. Shalinsky, G. Thurston, G. D. Yancopoulos, et al. Inhibition of Vascular Endothelial Growth Factor (VEGF) Signaling in Cancer Causes Loss of Endothelial Fenestrations, Regression of Tumor Vessels, and Appearance of Basement Membrane Ghosts Am. J. Pathol., July 1, 2004; 165(1): 35 - 52. [Abstract] [Full Text] [PDF]

				J. W. Park, R. S. Kerbel, G. J. Kelloff, J. C. Barrett, B. A. Chabner, D. R. Parkinson, J. Peck, R. W. Ruddon, C. C. Sigman, and D. J. Slamon Rationale for Biomarkers and Surrogate End Points in Mechanism-Driven Oncology Drug Development Clin. Cancer Res., June 1, 2004; 10(11): 3885 - 3896. [Full Text] [PDF]

				M. L. Wahl, T. L. Moser, and S. V. Pizzo Angiostatin and Anti-angiogenic Therapy in Human Disease Recent Prog. Horm. Res., January 1, 2004; 59(1): 73 - 104. [Abstract] [Full Text]

				L. Kostakoglu and S. J. Goldsmith PET in the Assessment of Therapy Response in Patients with Carcinoma of the Head and Neck and of the Esophagus J. Nucl. Med., January 1, 2004; 45(1): 56 - 68. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, B. Sweeney-Gotsch, R. Takamori, and D. J. McConkey The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts Mol. Cancer Ther., January 1, 2004; 3(1): 59 - 70. [Abstract] [Full Text]

				A. Abdollahi, K. E. Lipson, A. Sckell, H. Zieher, F. Klenke, D. Poerschke, A. Roth, X. Han, M. Krix, M. Bischof, et al. Combined Therapy with Direct and Indirect Angiogenesis Inhibition Results in Enhanced Antiangiogenic and Antitumor Effects Cancer Res., December 15, 2003; 63(24): 8890 - 8898. [Abstract] [Full Text] [PDF]

				P. Wells, T. Jones, and P. Price Assessment of Inter- and Intrapatient Variability in C15O2 Positron Emission Tomography Measurements of Blood Flow in Patients with Intra-abdominal Cancers Clin. Cancer Res., December 15, 2003; 9(17): 6350 - 6356. [Abstract] [Full Text] [PDF]

				G R Laking and P M Price Positron emission tomographic imaging of angiogenesis and vascular function Br. J. Radiol., December 1, 2003; 76(suppl_1): S50 - S59. [Abstract] [Full Text] [PDF]

				S M Galbraith Antivascular cancer treatments: imaging biomarkers in pharmaceutical drug development Br. J. Radiol., December 1, 2003; 76(suppl_1): S83 - S86. [Full Text] [PDF]

				M. E. Daly, A. Makris, M. Reed, and C. E. Lewis Hemostatic Regulators of Tumor Angiogenesis: A Source of Antiangiogenic Agents for Cancer Treatment? J Natl Cancer Inst, November 19, 2003; 95(22): 1660 - 1673. [Abstract] [Full Text] [PDF]

				Q.-T. Le and A. J. Giaccia Therapeutic Exploitation of the Physiological and Molecular Genetic Alterations in Head and Neck Cancer Clin. Cancer Res., October 1, 2003; 9(12): 4287 - 4295. [Abstract] [Full Text] [PDF]

				S. M. Plum, A. D. Hanson, K. M. Volker, H. A. Vu, B. K. L. Sim, W. E. Fogler, and A. H. Fortier Synergistic Activity of Recombinant Human Endostatin in Combination with Adriamycin: Analysis of in Vitro Activity on Endothelial Cells and in Vivo Tumor Progression in an Orthotopic Murine Mammary Carcinoma Model Clin. Cancer Res., October 1, 2003; 9(12): 4619 - 4626. [Abstract] [Full Text] [PDF]

				R. S. Herbst, L. A. Hammond, D. P. Carbone, H. T. Tran, K. J. Holroyd, A. Desai, J. I. Williams, B. N. Bekele, H. Hait, V. Allgood, et al. A Phase I/IIA Trial of Continuous Five-Day Infusion of Squalamine Lactate (MSI-1256F) Plus Carboplatin and Paclitaxel in Patients with Advanced Non-Small Cell Lung Cancer Clin. Cancer Res., September 15, 2003; 9(11): 4108 - 4115. [Abstract] [Full Text] [PDF]

				S. Williams, C. Pettaway, R. Song, C. Papandreou, C. Logothetis, and D. J. McConkey Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts Mol. Cancer Ther., September 1, 2003; 2(9): 835 - 843. [Abstract] [Full Text] [PDF]

				J. J. Erasmus, G. W. Gladish, L. Broemeling, B. S. Sabloff, M. T. Truong, R. S. Herbst, and R. F. Munden Interobserver and Intraobserver Variability in Measurement of Non-Small-Cell Carcinoma Lung Lesions: Implications for Assessment of Tumor Response J. Clin. Oncol., July 1, 2003; 21(13): 2574 - 2582. [Abstract] [Full Text] [PDF]

				J. H. M. Schellens and M. J. Ratain Endostatin: Are the 2 Years Up Yet? J. Clin. Oncol., September 15, 2002; 20(18): 3758 - 3760. [Full Text] [PDF]

				R. S. Herbst, K. R. Hess, H. T. Tran, J. E. Tseng, N. A. Mullani, C. Charnsangavej, T. Madden, D. W. Davis, D. J. McConkey, M. S. O'Reilly, et al. Phase I Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors J. Clin. Oncol., September 15, 2002; 20(18): 3792 - 3803. [Abstract] [Full Text] [PDF]