Significance: In 2008 the American Cancer Society predicted that 28,660 men will die from prostate cancer making it the second leading cause of cancer death in men. Bone is an extremely common site for prostate cancer metastasis. Prostate to bone metastases promote bone growth and destruction by manipulating normal host cells of the bone known as osteoblasts osteoclasts respectively. As a result, the patient often experiences intense pain, spontaneous fractures and morbidity that dramatically affect his quality of life. Prostate to bone metastases are incurable and the current treatment options are limited. In order to identify new therapeutic targets, a comprehensive understanding of how the prostate tumor cells communicate with the normal bone cells to induce bone growth and destruction is required. Rationale: We have generated a unique animal model of prostate tumor induced bone growth and destruction that accurately mimics the human disease. We have used the model to analyze the expression of thousands of genes in prostate bone tumors and have found that several enzymes known as matrix metalloproteinases (MMPs) are present at high levels (MMP-2, MMP-3, MMP-7, MMP-9 and MMP-13) and that they are predominantly expressed by the normal bone cells. MMPs are considered matrix 'bulldozers'but the PI using emerging data proposes a new concept that MMPs can facilitate cell-cell communication by altering the activity and availability of key substrates responsible for prostate cancer induced bone formation and destruction, namely parathyroid related peptide (PTHrP), receptor activator of nuclear kappa B ligand (RANKL) and transforming growth factor beta (TGF?). Based on these observations, we hypothesize that individual host derived MMPs are key contributors to prostate tumor induced bone destruction and bone formation by virtue of their ability to regulate the activity of factors that control prostate cancer-bone communication. Approaches:
In Specific Aim 1, we will use MMP 'knockout'animals test the contribution of these individual bone derived MMPs to prostate tumor induced bone destruction and formation using animal models that mimic the human disease.
In Specific Aim 2, we will determine how MMPs can impact prostate tumor induced changes in the bone by controlling the bioactivity and bioavailability of PTHrP and RANKL and TGF?. Innovation and Impact: The proposed study has several innovations;1) It will be the first to explore the contribution of individual host derived MMPs to prostate tumor induced bone formation/destruction using animal models that mimic the human disease;2) It will be the first to explore the impact of host MMPs on the bioactivity of PTHrP, RANKL and TGF? in the prostate tumor-bone microenvironment. The results of our proposed studies will enhance our understanding of basic tumor-bone biology, change the concept of the field as to how MMPs work and will reveal potentially new therapeutic targets that can be used to treat men with prostate to bone metastases.
In a process described as the vicious cycle, prostate to bone metastases induce areas of extensive bone formation and destruction by manipulating the normal host cells of the bone, osteoblasts and osteoclasts respectively. The proposed studies will investigate how individual matrix metalloproteinases (MMPs) expressed by the host facilitate the progression of the vicious cycle by regulating the bioactivity and bioavailability of growth factors and cytokines such as parathyroid hormone related peptide (PTHrP), receptor activator of nuclear kappa B ligand (RANKL) and transforming growth factor ? (TGF?). This studies will 1) enhance our basic understanding of tumor bone biology and provide new insights into the roles for MMPs in the tumor bone microenvironment;2) identify novel MMP substrates, the products of which can potentially be new therapeutic targets and 3) will provide a rationale for the development of highly selective MMP inhibitors that lack the deleterious side effects noted with broad spectrum MMP inhibitors.
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|Luhach, Ihor; Idiyatullin, Djaudat; Lynch, Conor C et al. (2014) Rapid ex vivo imaging of PAIII prostate to bone tumor with SWIFT-MRI. Magn Reson Med 72:858-63|
|Cook, Leah M; Shay, Gemma; Araujo, Arturo et al. (2014) Integrating new discoveries into the ""vicious cycle"" paradigm of prostate to bone metastases. Cancer Metastasis Rev 33:511-25|
|Tauro, Marilena; McGuire, Jeremy; Lynch, Conor C (2014) New approaches to selectively target cancer-associated matrix metalloproteinase activity. Cancer Metastasis Rev 33:1043-57|
|Gallaher, Jill; Cook, Leah M; Gupta, Shilpa et al. (2014) Improving treatment strategies for patients with metastatic castrate resistant prostate cancer through personalized computational modeling. Clin Exp Metastasis 31:991-9|
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