Preclinical Evaluation of Serine/Threonine Kinase Inhibitors Against Prostate Cancer Metastases
Abstract
Bone is a rich store of growth factors that stimulate metastatic cancer cells. TGFbeta in bone increases tumor secretion of factors that activate bone remodeling, fueling a vicious cycle, driving growth and survival of prostate bone metastases. TGFbeta signals through a receptor with two serine/threonine kinases subunits and, further downstream, partly through another serine/threonine kinase, p38 MAPK. We hypothesized that kinase inhibitors would reduce prostate cancer metastasis to bone. Two orally active inhibitors were tested in animal models of prostate cancer bone metastases. Aim 1 testeda TGFbeta receptor I kinase inhibitor against two human prostate cancer models of skeletal metastases in mice. Aim 2 found a molecular target of the inhibitors in prostate cancer cells: PMEPA1. Aim 3 was to test the efficacy of combined TGFbeta receptor I and p38 MAPK inhibitors against two prostate cancer models in vivo, but only the former class of drug was effective. TGFbeta inhibitors may be clinically useful against osteolytic bone metastases.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2007
- Accession Number
- ADA490313
Entities
People
- Theresa Guise
Organizations
- University of Virginia