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Tissue Examination to Monitor Antiangiogenic Therapy: a Phase I Clinical Trial with Endostatin1

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Tissue Examination to Monitor Antiangiogenic Therapy: a Phase I Clinical Trial with Endostatin1 3366 Vol. 7, 3366–3374, November 2001 Clinical Cancer Research Tissue Examination to Monitor Antiangiogenic Therapy: A Phase I Clinical Trial with Endostatin1 Christoph Mundhenke, James P. Thomas, INTRODUCTION George Wilding, Fred T. Lee, Fred Kelzc, Neoplasms depend on the formation of new of blood Rick Chappell, Rosemary Neider, vessels (angiogenesis) for continued growth and metastatic Linda A. Sebree, and Andreas Friedl2 spread. Without angiogenesis, tumors remain small and do not threaten the life of the host (1). In normal resting tissues, Comprehensive Cancer Center [C. M., J. P. T., G. W., F. T. L., F. K., R. C., R. N., A. F.], Department of Pathology and Laboratory where blood vessel growth is minimal, angiogenesis is con- Medicine [L. A. S., A. F.], and Department of Biostatistics [R. C.], trolled by a balance of angiogenic stimulators and inhibitors. University of Wisconsin Madison, Wisconsin 53792; and Department This balance is perturbed in tumors to favor angiogenesis of Obstetrics and Gynecology, University of Kiel, 24105 Germany either by overproduction of angiogenesis inducers or by lack [C. M.] of inhibitors (2). Recently, several naturally occurring angiogenesis inhibi- ABSTRACT tors have been identified. The most potent inhibitor appears to Purpose: The purpose of this study was to determine the be endostatin, the COOH-terminal proteolytic fragment of the effect of the angiogenesis inhibitor endostatin on blood ves- basement membrane component collagen XVIII (3). In a xeno- sels in tumors and wound sites. transplantation model, endostatin administration leads to pro- Experimental Design: In a Phase I dose escalation study, nounced tumor regression, suggesting that the peptide induces cancer patients were treated with daily infusions of human regression of existing blood vessels in addition to preventing the recombinant endostatin. Tumor biopsies were obtained growth of new ones (3, 4). Preclinical experiments targeting prior to and 8 weeks after initiation of treatment. Blood endogenous tumors have shown less dramatic results. The vessel formation in nonneoplastic tissue was evaluated by mechanism of action of endostatin is unclear. It inhibits endo- creating a skin wound site on the arm with a punch biopsy thelial cell proliferation in vitro (5, 6). Different investigators device. The wound site was sampled with a second biopsy have proposed interference with vascular endothelial cell after a 7-day interval. This sequential biopsy procedure was growth factor and fibroblast growth factor-2 (basic fibroblast performed prior to and 3 weeks after initiation of endostatin growth factor) pathways (7), induction of endothelial cell apo- treatment. Vascular density, endothelial cell kinetics, and ptosis (8, 9), and inhibition of matrix metalloproteases (10). blood vessel maturity were determined in tumor and skin Inhibition of endothelial cell migration by modulating c-myc wound samples. The ultrastructure of tumor blood vessels levels has also be proposed (11). Endostatin possesses a prom- was examined by electron microscopy. inent heparan sulfate binding domain (12), but at present it is Results: As expected, the tumors were of variable vas- unresolved whether this domain is required for antiangiogenic cular density. Skin wounding induced a vascular granula- tion tissue containing a high percentage of proliferating activity (6, 13, 14). We have described the ability of endostatin endothelial cells. The proportion of immature blood vessels to interact with vascular basement membranes independent of was high in tumors and in wound sites and low in normal its heparan sulfate binding domain (15). skin. No statistically significant difference was detected be- Recent successes in producing active human recombinant tween pretreatment and treatment samples of tumors and of endostatin in yeast in large quantities have allowed testing of skin wounds for any of the parameters tested. this protein in early clinical studies (16, 17). Antiangiogenic Conclusions: Endostatin treatment was not associated treatment strategies offer a number of compelling advantages with any recognizable vascular changes in tumor samples over conventional cytotoxic cancer therapies that have been and did not perturb wound healing at the doses and the highlighted in recent reviews (18). Briefly, endothelial cells, the treatment schedule used. drug targets, are readily accessible to pharmacological agents. The ratio of tumor cells to endothelial cells has been estimated as 100:1 (1), leading to the expectation of an amplified antitu- mor effect when endothelial cells are successfully inhibited. Probably most importantly, in contrast to genetically unstable Received 3/1/01; revised 7/2/01; accepted 7/31/01. tumor cells, endothelial cells are genetically stable, making it The costs of publication of this article were defrayed in part by the unlikely that antiangiogenic agents would induce drug resist- payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to ance (19). This latter argument is powerfully supported by indicate this fact. preclinical studies (4). 1 This study was supported by NIH Grant UO1 CA62491. Designing clinical trials with angiogenesis inhibitors is 2 To whom requests for reprints should be addressed, at University of hampered by the fact that it is very difficult to determine the Wisconsin, Department of Pathology, Clinical Sciences Center K4/850, 600 Highland Avenue, Madison, WI 53792. Phone: (608) 265-9283; optimal dose and administration regimen. Treatment with cyto- Fax: (608) 265-6215; E-mail: [email protected]. toxic drugs has typically been optimized by determining the Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 3367 MTD.3 Pure antiangiogenic agents would be expected to have a low toxicity, and the MTD may be far higher than the biolog- ically optimal dose. In addition, administration of the MTD of a biological inhibitor such as endostatin may not be economically feasible. Ideally, antiangiogenic therapy should be titrated based on biological end points. There are no established assays for measuring angiogenesis (or its inhibition) in humans. In animal models, corneal angiogenesis assays are the gold standard, but skin angiogenesis assays have also been used successfully (20). A skin wounding assay has also recently been described in humans (21, 22). Blood vessel formation in healing wounds as a surrogate angiogenesis assay may not exactly mirror tumor Fig. 1 Time schedule for biopsies relative to treatment. Two pairs of angiogenesis, but it may provide important information on an- skin biopsies were taken: one prior to initiation of endostatin therapy, tiangiogenic activity and predict delayed wound healing as a and one 3 weeks after the beginning of treatment. Tumor biopsies were potential adverse effect of angiogenesis inhibitors. obtained before and 8 weeks into endostatin treatment. Treatment was Here we report on the results of blood vessel examination interrupted during the 5th week and then reinstituted beyond 8 weeks until tumor progression. in tissues of wound sites and tumors in patients of an NCI- sponsored Phase I dose escalation trial with the angiogenesis inhibitor endostatin at the University of Wisconsin Comprehen- sive Cancer Center. Blood vessels were characterized quantita- and one half was fixed in 10% buffered formalin and routinely tively and qualitatively by determining vascularity, endothelial embedded in paraffin. The other half was divided into a small cell kinetics, and blood vessel maturity. Comprehensive analysis sample for electron microscopy, and the rest was embedded in of blood vessels in situ may serve as a model for future trials OCT compound and snap-frozen to Ϫ70°C. with antiangiogenic agents and help define surrogate end points Immunohistochemical Labeling. Four-␮m-thick paraf- for such studies. fin sections on “Plus” slides were baked, deparaffinized, and rehydrated. Heat-induced epitope retrieval was performed on all MATERIALS AND METHODS slides by immersion of the slides in 1 mM EDTA (pH 8) and Patients and Treatment. Twenty-one cancer patients incubation in an electric pressure cooker (BioCare Medical, with nonhematological malignancies without brain metastases Walnut Creek, CA) for 3 min at 25 psi. The slides were placed who had progressed on standard therapies were recruited for a on the ES automated immunohistochemical stainer (Ventana Phase I dose escalation study testing the tolerability of the Medical Systems, Tucson, AZ). angiogenesis inhibitor endostatin. Human recombinant endosta- Ki67 labeling was performed using a monoclonal antibody tin produced in yeast (Entremed, Rockville, MD) was adminis- (clone 7B11; Zymed Laboratories, San Francisco, CA) at a 1:75 tered by daily infusions at six dose levels (30–300 mg/m2) until dilution for 28 min at 42°C, followed by an amplification kit and progression. Informed consent and Institutional Review Board the diaminobenzidine basic detection system (both Ventana approval were obtained for all procedures. Medical Systems). Labeling for MSA required pretreatment Skin Biopsies. Two sequential skin biopsies were per- with protease 3 (Ventana). Anti-MSA mouse monoclonal anti- formed with a 4-mm punch biopsy device (Accuderm) in the body (clone HHF35; BioCare) was applied as a prediluted same location on the upper arm, to assess blood vessel formation
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