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


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.


CONCLUSIONS
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.
Herbst
Roy S
RS
Department of Thoracic and Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. rherbst@mdanderson.org
Mullani
Nizar A
NA
Davis
Darren W
DW
Hess
Kenneth R
KR
McConkey
David J
DJ
Charnsangavej
Chusilp
C
O'Reilly
Michael S
MS
Kim
Hyung-Woo
HW
Baker
Cheryl
C
Roach
Jennifer
J
Ellis
Lee M
LM
Rashid
Asif
A
Pluda
James
J
Bucana
Corazon
C
Madden
Timothy L
TL
Tran
Hai T
HT
Abbruzzese
James L
JL
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000032:analysis*; D017252:CD3 Complex / Q000378:metabolism; D003094:Collagen / Q000378:metabolism / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D043169:Endostatins; D004727:Endothelium / Q000166:cytology / Q000187:drug effects; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D020287:In Situ Nick-End Labeling; D007834:Lasers; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010446:Peptide Fragments / Q000378:metabolism / Q000627:therapeutic use*; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000627:therapeutic use; D014055:Tomography, Emission-Computed
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D017252:CD3 Complex; D043169:Endostatins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019788:Fluorodeoxyglucose F18; D003094:Collagen