Gary Balian, PhD
Biochemistry of extracellular matrix molecules, role of the bone microenvironment in normal and metastatic cell growth
This project was conceived by three investigators, Drs. Gary Balian and Jay Fox (University of Virginia) and Dr. Robert Sikes (University of Delaware) working together to discover the molecular mechanism of interaction between prostate cancer cells and bone. The interaction in vitro and in vivo between prostate cancer cells and mesenchymal cells from bone marrow stroma that exhibit osteoprogenitor characteristics has lead to adhesion studies with prostate cancer cells. In order to unravel the molecular mechanisms that are involved in cancer cell interaction with bone, they have used a phage display peptide library to identify a number of peptides that target bone and bone marrow. An investigation of these peptides is being pursued with the objectives of determining tissue and cell specificity of bone targeting peptides, 2) Peptide effects on adhesion, invasion and migration by prostate cancer cells, and, 3) Cell membrane and extracellular matrix target identification. In experiments using a phage display library in vivo, a number of peptide sequences have been identified by DNA sequencing. The sequences were detected repeatedly in phage that was isolated from bone and bone marrow. The objective is to establish if the peptides corresponding to the DNA sequences target cells within bone and bone marrow, such as osteoblasts, osteoblast progenitors i.e. mesenchymal cells in bone marrow stroma, hematopoietic cells or bone marrow endothelial cells in the endosteal bring. The effects of peptides on prostate cancer cell adhesion, invasion and migration are being investigated. Receptors for the peptide sequences will be determined by affinity chromatography and by peptide mapping of cell membrane proteins and extracellular matrix molecules. Targeting specificity will be examined by binding the phage display peptides in vivo and in vitro to bone, musculoskeletal tissues other than bone, and to other, non musculoskeletal tissues such as spleen, lung and liver. The therapeutic potential for peptides that target bone is a distinct possibility. If individual peptides are found to bind specifically to cells or extracellular matrix in bone, their potential as carriers of pharmacologic agents, such as polypeptide factors and therapeutic genes, can be explored Determination of the effects of bone tropic peptides on cell attachment and invasion is relevant to the cancer field. Identification of targeting peptides and their ligands will provide basic information towards understanding the mechanisms of cell metastasis to bone. Their analysis of targeting peptides; and their ligands will provide basic information on the mechanism of metastasis to bone and the therapeutic value of the peptides for the prevention of metastases and for drug delivery.