Nearly 200, 000 women are diagnosed with breast cancer each year in the United States. The majority of patients with advanced breast cancer will develop bone metastasis resulting in bone destruction causing severe bone pain and pathological fractures. The goal of this proposal is to develop a therapeutic approach that will destroy the primary tumor, and inhibit the bone metastasis. We will combine the oncolytic effects of an adenoviral vector along with selective expression of soluble form of TGFbeta receptor II fused with Fc (sTbetaRIIFc). TGFbeta pathway is an attractive target because high levels of TGFbeta protein enhance tumor invasion and bone metastasis. It is hypothesized that in the adenoviral vector 01/07sTbetaRIIFc, viral backbone will be oncolytic to the tumor cells and the vector-mediated production of sTbetaRIIFc and secretion into the blood will block the effects of TGFbeta.
Aim 1). To investigate 01/07sTbetaRIIFc replication, 01/07sTbetaRIIFc-mediated sTbetaRIIFc production and inhibition of osteoclast formation in vitro. Various breast cancer cells and normal human cells will be infected with 01/07sTbetaRIIFc and analyzed for viral replication and sTbetaRIIFc production. The effect of sTbetaRIIFc expression on the formation of osteoclast cells responsible for bone resorption will be investigated.
Aim 2). To investigate 01/07sTbetaRIIFc-mediated inhibition of bone metastasis and osteolysis in human breast cancer xenograft models in vivo. MDA-MB-231 cells will be used to produce subcutaneous tumors in nude mice. The 01/07sTbetaRIIFc will be injected into the tumors and viral replication, and the production and release of sTbetaRIIFc into the blood will be investigated. The adenoviral distribution in non-tumor organs and a set of liver enzymes, cytokines, and chemokines will be examined. To evaluate bone metastasis, animals bearing subcutaneous tumors will be injected with MDA-MB-231 cells into the left cardiac ventricle that results in bone metastasis. Recombinant viral vector will be injected into the subcutaneous tumors and radiographic measurements of osteolytic lesion area, microCT scan to quantify osteolysis, and histomorphometric analysis of the bones to quantify the tumor burden will be investigated.
| Wang, Zhen-Guo; Zhao, Wenli; Ramachandra, Murali et al. (2006) An oncolytic adenovirus expressing soluble transforming growth factor-beta type II receptor for targeting breast cancer: in vitro evaluation. Mol Cancer Ther 5:367-73 |
