Integrative systems modeling of prostate cancer bone metastases
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    Integrative systems modeling of prostate cancer bone metastases
    Investigators: David W Smith1, Bruce S Gardiner1, Peter Pivonka1, N. Bhowmick2, G.R. Mundy3
    Institutions:
      1Dept of Environmental Engineering, University of Western Australia, WA, Australia
      2Biomedical Engineering, University of Sydney , NSW, Australia
      3 Center for Bone Biology, Vanderbilt University , TN , USA

    Sponsor: Prostate Cancer Foundation Australia (PCFA)
    Project ID: Concept Grant
    Email contact:
      david.wsmith@uwa.edu.au
      bgardine@unimelb.edu.au
      peter.pivonka@uwa.edu.au

    Project Description
    Bone metastasis occurs in approximately 90% of prostate cancer related deaths. The tumour-bone microenvironment is critical to cancer progression as there are reciprocal and interlocking networks of interactions between tumour cells and bone stroma which can support tumour progression and modify bone integrity. The complexity of these interactions creates the potential for both positive feedback (vicious cycles) and negative feedback (inhibiting tumour progression) along with a spectrum of bone volume changes. This complexity also makes predicting the behaviour of this interaction network beyond human intuition.

    To find effective strategies to understand and manipulate this tumour-bone microenvironment we need a method of integrating the known key interactions and processes into a system-level model. Our experience with other complex biological systems (e.g. IGF-1 uptake in articular cartilage, Wnt/¦Ãatenin signalling in colorectal cancer, renal oxygen regulation) is that computational modelling can provide therequired integrating platform or framework to do this.

    Therefore the key aim here is to extend our existing computational model describing interactions between osteoblasts and osteoclasts that occurs during bone remodeling to include interactions with prostate cancer derived cells. We will build a computation platform that can be employed in understanding the progression of prostate metastasis in bone. Much is known about the interactions between epithelial cells and mesenchymal cells in the prostate, and how this changes in the development of a tumor. Likewise in the bone, much is known about the interactions between osteoblastic and osteoclastic cell lineages. The addition of prostatic tumor cells and prostatic stromal cells can have a profound effect on the bone microenvironment, disrupting normal cell-cell signaling and leading to bone lysis and bone formation. We propose to bring these known interactions together in a computational model, and use the model to try and understand the likely outcomes on tumour progression and bone volume changes. We will extend the model to reflect state-of-the-art knowledge on aspects of the biology that are likely to be most important. The description of the project proposal here focuses on model construction and interrogation.

    Collaborators:
    Prof Gregory R Mundy - Director of the Centre for Bone Biology at Vanderbilt University http://bonecenter.mc.vanderbilt.edu/mundy - is an expert in bone biology and cancer research. Research interests in Dr. Mundy's group include drug discovery in osteoporosis, the effects of tumors on the skeleton, osteoclast and osteoblast biology and development of the skeleton. Dr. Mundy is currently the principal investigator on 3 R01 grants, one VA Merit Review grant, and a National Institute funded Program Project Grant on the effects of tumors on the skeleton. He is in the top 2% of all NIH awardees in terms of extra-mural funding over the past 25 years. Dr. Mundy's publications number more than 500 papers and book chapters, and he has published 2 monographs on calcium homeostasis and bone remodeling and its disorders.
    Prof Neil Bhowmick - Dept of Civil & Environmental Engineering & Geodetic Science at the Ohio State University http://www.ceegs.ohio-state.edu/faculty/fox is mainly interests is in geotechnical engineering with emphasis on geoenvironmental engineering, flow through porous media, consolidation, geosynthetics, soft soils, retaining structures, and slope stability.

    Research Outcomes:

      2009 (Year 1)
      2010 (Year 2)
    List of current students:
      Yan Wang
    List of publications
      Journal papers
      Presentations at conferences (provide pdf or ppt files)
     

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The University of Western Australia
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Last updated: December 02 2009 08:35:29.