Background: Prostate cancer is a major cause of suffering in American men. Despite significant advances in our understanding and management of this disease, a large number of men develop progressive, so-called "castrate resistant" and metastatic prostate cancer. Although a number of mechanism have been postulated to cause advanced prostate cancer, no single pathway can explain all advanced disease. Our group has recently identified one potential target for treating advanced prostate cancer - N-cadherin. N-cadherin is a cell surface protein that is involved in a process called epithelial to mesenchymal transition (EMT). In this process, epithelial cancer cells acquire the shape and behavior of stromal cells, such as fibroblast. Cells undergoing EMT are more motile and metastatic than normal epithelial cells. In our preliminary studies, we show that N-cadherin is expressed in a significant percentage of advanced prostate cancers. We show that addition of this gene causes prostate cancer cells to become more invasive and resistant to removal of testosterone. In animal models, these cells are metastatic and castrate resistant. We show that N-cadherin turns on a number of downstream signaling pathways, such as the NF-kappaB pathway, which is implicated in stem cell function, metastasis, and hormone resistance. We generated antibodies that bind to N-cadherin and show that these antibodies can suppress the growth and metastasis of prostate cancers in animal models. These promising studies suggest that N-cadherin is a novel and promising target for treating prostate cancer.

Specific Aims: The goal of this grant is to understand the mechanisms by which N-cadherin causes metastasis, EMT, and castrate resistance. By elucidating these pathways, we plan to develop combination therapies that will block prostate cancer progression more effectively than N-cadherin antibodies alone. In Aim 1, we will evaluate the components of the NF-kappaB pathway activated by N-cadherin, examine the interaction of this pathway with other known pathways affected by N-cadherin, such as androgen receptor and the Akt pathways. In Aim 2, we will determine which parts of the N-cadherin protein govern the signaling pathways studies in Aim 1 in order to identify the best part of N-cadherin to target with antibodies (either the ones we have or new ones). In Aim 3, we will use the information from the first two aims to test individual antibodies and combinations of antibody with novel anti-cancer agents targeting the downstream pathways influenced by N-cadherin to treat prostate cancer in preclinical models. Together, these studies will provide insight into advanced prostate cancer and develop rational therapeutic strategies to take into the clinic.

Study Design: In Aim 1, we will first determine the components of the NF-kappaB pathways that are activated by N-cadherin. We will then assess the interactions between N-cadherin, NF-kappaB, and the AR signaling pathways. Finally, we will determine the interactions between blockade of N-cadherin and the downstream pathways alone and in combination on the growth of prostate cancer in tissue culture. In Aim 2, we will construct N-cadherin molecules in which individual parts of the protein are replaced by those from another gene. By replacing individual parts of N-cadherin and then examining how the reconstituted molecule functions, we will be able to determine which parts of the protein are responsible for which behaviors. In Aim 3, we will translate the lessons of Aims 1 and 2 into preclinical studies of individual and combination therapies to target N-cadherin. In vivo studies will assess the efficacy of these therapies on tumor growth, metastasis, and castration resistance.

Relevance: This synergy grant is highly relevant to the care of men with advanced prostate cancer. It is based on observations of N-cadherin expression in advanced cancers and preliminary studies that clearly implicate N-cadherin (and associated EMT) in prostate cancer growth, angiogenesis, invasion, metastasis, and castrate resistance. The overall goal of the project is to develop rational strategies combining N-cadherin antibodies and other targeted agents to treat advanced prostate cancer. We believe this is a highly promising and innovative proposal with potentially high impact on prostate cancer.