PRIMARY XENOGRAFTS OF HUMAN TISSUE AS SURROGATES OF CANCER IN SITU


Year of Award:
2009
Award Type:
R43
Project Number:
CA137737
RFA Number:
RFA-CA-08-011
Technology Track:
Molecular & Cellular Analysis Technologies
PI/Project Leader:
ZWICK, MICHAEL G
Other PI or Project Leader:
N/A
Institution:
ANDROBIOSYS, INC.
AndroBioSys, Inc. is dedicated to the development of human tissue-based in vivo tools capable of selecting better targeted agents for clinical trials by improved preclinical testing. AndroBioSys has developed the technology for reproducible implantation of primary xenografts of benign and malignant human prostate and kidney tissue. Xenografts have been established from over two hundred and fifty successive fresh surgical specimens and are characterized by maintenance of the tissue architecture of the tissue in the human donor, including the maintenance of a completely human vascular network and tissue microenvironment. The vascular endothelial cells of primary xenografts of benign and malignant human prostate tissue demonstrate active angiogenesis, express functional androgen receptor protein, and undergo a wave of apoptotic death upon androgen deprivation that precedes by several days the wave of apoptotic death of prostate epithelial or prostate cancer epithelial cells. In contrast, while the endothelial cells in primary xenografts of benign human kidney tissue or human renal cell carcinoma tissue are of human origin, the endothelial compartment demonstrates minimal angiogenic potential, does not express AR and does not undergo apoptotic death in response to androgen deprivation. Lastly, in support of the in vivo xenograft model, AndroBioSys has developed the expertise to establish primary cultures of human epithelial, stromal and endothelial cells from fresh surgical specimens of benign and malignant prostate and kidney tissue for prediction and/or verification of in vivo studies in matching primary xenografts. The goal of this application to the IMAT Program is to validate this in vitro/in vivo pre-clinical model system as a tool for analysis at the molecular level of: inter-individual differences in host biology; differences between the biology of individual cancers; and inter-individual differences in the host micro- environmental compartments. In addition, the Phase I program will evaluate the utility of this model for analysis of treatment modalities that target the human endothelial cell/vascular barrier, as a mechanism to modulate the bio-availability and response to therapeutic modalities, focusing on molecular endpoints measurable at the cellular, tissue and systemic (host serum) levels.