Principal Investigator/Program Director (Last, First, Middle):
Keller, Evan T./Chung, Leland
DESCRIPTION: See instructions. State the application’s broad, long-term objectives and specific aims, making reference to the health relatedness of
the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe
the rationale and techniques you will use to pursue these goals.
In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this
description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE
PROVIDED.
TITLE: Plasticity and targeting of prostate cancer in tumor microenvironment
ABSTRACT: One of the hallmarks of cancer is the ability to invade the stroma matrices. The invasive front
of cancer cells is characterized by morphologic and biochemical transition, such as epithelial to
mesenchymal transition (EMT), and the reciprocal cellular interaction and signaling between tumor and
stroma. Studies from our laboratory using cell culture and animal models, validated by clinical specimens,
suggests that upon tumor-stroma interaction, certain irreversible genetic and gene expression changes can
be provoked The overarching theme of this proposal is that prostate cancer growth and metastasis is
determined and maintained by tumor-stroma interaction mediated by key regulatory signaling pathways. By
exploiting these signaling pathways and their interruption, novel therapeutics can be developed. Three
Specific Aims are proposed:
Specific Aim 1: To isolate and characterize prostate and bone derived stromal fibroblasts for the evaluation
of the cell signaling pathways that promotes prostate cancer growth and progression. The hypothesis to be
tested is that prostate fibroblasts derived from different zonal origin, and bone cells derived from metastatic
prostate cancer patients with different tumor burdens have differential inductive potential for the growth and
progression of prostate cancer in mice. We will define three paracrine/autocrine signaling mechanisms:
sonic hedgehog (SHH)/patched (Ptc)/GLI, β2 microglobulin (β2M)/protein kinase A (PKA)/cAMP responsive
element binding protein (CREBP), and PTEN/AKT/PI3K, in the tumor-stroma interaction models.
Specific Aim 2: To define the convergence of SHH/Ptc, β2M/PKA/CREB and PTEN/AKT/PI3K signaling
pathways in prostate cancer and stroma interaction model with specific emphasis on the ability of prostate
cancer cells to undergo EMT, to mimic the bone cells and to undergo permanent behavioral and
morphological changes to express stem cell-like genes. The hypothesis to be tested is that the phenotype
and genotype changes of tumor and stroma will be determined by specific signaling pathways. The
emphasis of this approach is to compare tumor-stroma interaction under 2- or 3-D co-culture conditions with
cell signaling pathways interrupted by pathway-specific inhibitors, such as cyclopamine, BK1740, and/or
semaphore SF-1126.
Specific Aim 3: To characterize the cross-talk of SHH/Ptc, β2M/PKA/CREB, and PTEN/AKT/PI3K in
transgenic mouse models and to design specific targeting strategies for the treatment of prostate cancer
local growth and bone metastases. The hypothesis to be tested in this Aim is that cross talk between these
cell signaling pathways promotes local prostate cancer growth, facilitates mesenchymal transition, and
increases cancer metastasis. The emphasis will be to establish and characterize transgenic mouse models
with selectively activated signaling pathways and targeting strategies to study the behavior of prostate
cancer cells in mice.
The proposed aim will interdigitate with other projects in the TME network for development of other
innovative technologies for improved visualization and detection of prostate cancer metastasis using
nanotechnology, and the construction of 3D chimeric cell culture models using precious human materials.
The
collectiveSITE(S)
advances
brought
these approaches will be translated into the clinic for the development of
PERFORMANCE
(organization,
city,by
state)
novel therapeutic approaches to improve the diagnosis and treatment of advanced prostate cancer in men.
Emory University, Atlanta, Georgia
PHS 398 (Rev. 04/06)
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Principal Investigator/Program Director (Last, First, Middle):
Keller, Evan T./Chung, Leland
KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below.
Start with Principal Investigator. List all other key personnel in alphabetical order, last name first.
Name
eRA Commons User Name
Organization
Role on Project
Chung, Leland
Emory University
Project Director
Durden, Donald
Hsieh, Chia-Ling
Emory University
Emory University
Co-Investigator
Co-Investigator
Zhau, Haiyen
Xie, Jingwu
Emory University
University of Texas
Co-Investigator
Consultant
OTHER SIGNIFICANT CONTRIBUTORS
Name
Organization
Role on Project
Human Embryonic Stem Cells
No
Yes
If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list:
http://stemcells.nih.gov/registry/index.asp. Use continuation pages as needed.
If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used.
Cell Line
PHS 398 (Rev. 04/06)
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Form Page 2-continued
Number the following pages consecutively throughout
the application. Do not use suffixes such as 4a, 4b.