Developmental Research Pilot Project
Robert Vessella, PhD, University of Washington
"Inhibition of Angiopoietin-2 in CaP Bone and Soft Tissue Tumors in SCID Mice"
Abstract
While chemotherapeutic strategies show some promise, there is at present no effective therapy for hormone refractory metastatic prostate cancer (PCa) that substantially prolongs survival. The reactive stroma and its associated vasculature are integral to the survival and growth of tumor epithelial cells at a metastatic site. In addition the development and maintenance of tumor vasculature is supported by stromal elements and the tumor itself.
Angiopoietin-2 is a key factor in promoting angiogenesis. Angiopoietin-2 expression has been related to histological grade, vascular density, and metastases, and is correlated with the occurrence of metastases at the time of diagnosis in PCa patients. We have determined that angiopoietin-2 is expressed in PCa bone and liver metastases whereas angiopoietin-1 is not. This shifts the angiogenic balance towards the pro-angiogenic angiopoietin-2. We have also observed significant differences in the expression of angiopoietin-2 in PCa tumor cells in bone vs liver metastases. Our data suggest that angiopoietin-2 may have a pivotal role in promoting angiogenesis in PCa and may be regulated by the tumor microenvironment. Thus we hypothesize that the inhibition of angiopoietin-2 activity in PCa metastasis will impede angiogenesis and thereby decrease tumor growth.
Ab536, a neutralizing antibody to angiopoietin-2, was shown to significantly inhibit tumor growth in A431, squamous cell carcinoma in vivo. We will block angiopoietin-2 activity (using Ab536) in established subcutaneous and intra-tibial PCa (C4-2B) xenografts in SCID mice. We will then determine the effects of Ab536 on tumor growth, angiogenesis, and bone remodeling in the animals. Our results will determine whether inhibiting angiopoietin-2 activity in a soft tissue and an osseous microenvironment will impede angiogenesis and PCa tumor growth in vivo.
