Hyaluronan Tumor Cell Interactions in Prostate Cancer Growth and Survival PRINCIPAL INVESTIGATOR:

The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. Hyaluronan is a high molecular weight polyanionic polysaccharide that is increased in more advanced prostate cancers. Tumor cell interaction with this polysaccharide by specific receptors CD44 and RHAMM promote tumor growth, survival and invasion. Work during the last funding period have further defined the mechanism of action of each of these receptors. Studies show that extracellular RHAMM acts a co-receptor for CD44, and the combined action of this receptor complex leads to sustained activation of the ERK 1,2 signal transduction pathway leading to enhance motility and produce patterns of gene transcription that are associated with invasion. Synthetic peptides have also been identified that can bind hyaluronan and inhibit the binding of this polysaccharide to its cognate receptors. These peptides inhibit tumor growth both in vitro and in vivo and the residues important for the activity of the peptides are being defined using nuclear magnetic resonance (NMR). Small molecule libraries that contain compounds which may mimic these peptides are also being interrogated for the ability to inhibit hyaluronan binding to RHAMM and CD44 and to inhibit tumor growth. The goal is to develop new therapeutic strategies for patients with invasive prostate cancer.