This proposal makes use of longitudinal non-invasive, high-resolution imaging and spectroscopy techniques, which were developed in my laboratory, in combination with extensive post mortem and in vitro analyses of Pten-based mouse prostate cancer (PCa) models, specifically designed for use in translational. The goals are to understand the biochemical and molecular pathogenesis of prostate cancer initiation and progression. Our long-term goal is to combine non-invasive imaging with ex vivo analyses to define potential biomarkers of PCa (e.g., prostate volume and biochemical shifts). This proposal will correlate morphometric and metabolic changes in the prostate with potential molecular markers of cell proliferation (e.g., cyclin D1, Ki-67) to further our understanding of the mechanisms of PCa initiation and progression to advanced stage cancer.
Aim 1. Determine the prostate growth volumetry in Pten-based in mouse models of PCa in vivo by MRI. Hypothesis. Longitudinal Diffusion Weighted Imaging and MR volumetry, in vivo, of PCa initiation and progression will allow for the non-invasive identification and quantification of morphometric changes in the prostate, over time.
Aim 2. Identify biochemical changes in the prostate epithelium in mice used in Aim 1 through in vivo MR spectroscopy performed on mouse PCa models. Hypothesis. In vivo MRS will aid in identifying biochemical markers of PCa progression in biologically relevant mouse models.
Aim 3. Determine the signaling pathways involved in the cross talk-between Pten and ErbB-2 during PCa initiation and progression. Hypothesis. Combined increases in cyclin D1 gene activity and Ki-67 nuclear staining represent molecular markers of PCa progression, and are associated with increased prostate size and choline:citrate ratios.
These Aims are focused on non-invasively quantifying the contributions of ErbB-2 and Pten on prostate size and metabolism in vivo and to use complementary post mortem analyses to further our understanding of the molecular mechanisms involved in both initiating PCa and in its progression. This proposal will explore the role that both genetics and age play in PCa, using properly controlled and adequately powered in vivo and ex vivo studies (analyses which cannot be performed in humans). In addition, complementary in vitro experiments using human PCa cell lines allow for both validation and extension of the mouse data, with respect to mechanism of signal transduction and target gene expression. Our comprehensive approach to imaging and cancer has direct applicability to the better understanding the mechanisms of clinical PCa.
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|Ringer, Lymor; Sirajuddin, Paul; Heckler, Mary et al. (2011) VMY-1-103 is a novel CDK inhibitor that disrupts chromosome organization and delays metaphase progression in medulloblastoma cells. Cancer Biol Ther 12:818-26|
|Vissapragada, Sarada; Ghosh, Anup; Ringer, Lymor et al. (2010) Dietary n-3 polyunsaturated fatty acids fail to reduce prostate tumorigenesis in the PB-ErbB-2 x Pten(+/-) preclinical mouse model. Cell Cycle 9:1824-9|
|Ringer, Lymor; Sirajuddin, Paul; Yenugonda, Venkata Mahidhar et al. (2010) VMY-1-103, a dansylated analog of purvalanol B, induces caspase-3-dependent apoptosis in LNCaP prostate cancer cells. Cancer Biol Ther 10:320-5|
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