The treatment of oncogenic lesions residing in bone has advanced with an ever increasing array of therapies;however, response to treatment is considered """"""""unmeasurable"""""""" according to existing clinical response criteria (RECIST). Therefore, the biomarkers available for assessment of treatment response used by oncologists and radiologists to monitor the response of cancer in the bone needs a quantum advance. Underlying this need is that bone is a common site of residence of metastatic tumors derived from prostate cancer. Imaging using skeletal scintigraphy, plain radiography, computed tomography, or magnetic resonance imaging remains essential, with positron emission tomography or single-photon emission computed tomography having potential applicability for diagnosing the presence of bone metastases. However, no consensus exists as to the best modality for diagnosing these lesions or for assessing response to treatment. In this application, we hypothesize that changes in tumor microenvironment (e.g. cell density) will occur early following initiation of successful therapy. Since water within tumor cells is in a restricted environment versus extracellular water, loss of cell membrane integrity has been shown to reduce the diffusion barriers (e.g. restrictions) of water within the tumor, which can be quantified using diffusion MRI. We have recently developed the functional diffusion map (fDM) which is an imaging biomarker analytical approach for quantifying therapeutic-induced changes in the Brownian motion of water within tumor tissue. In this application, we will evaluate the capability of the fDM imaging biomarker for quantification of treatment response in a mouse model of metastatic prostate cancer to the bone. Treatments to be evaluated include ionizing radiation, cytotoxic chemotherapy (docetaxel), anti-angiogenic therapy, molecularly targeted agents and androgen deprivation. Animal studies will provide the data needed to support the use of the fDM imaging biomarker for quantification of the effectiveness of key therapeutic interventions. Clinical studies will also be undertaken to assess the fDM biomarker as an early treatment response marker for outcome assessment in patients treated with androgen deprivation or docetaxel chemotherapy. The ultimate goal of this application is to evaluate the fDM method as a viable, quantifiable imaging biomarker for early monitoring o treatment response in patients with metastatic prostate cancer to the bone.

Public Health Relevance

Overall, this research effort will provide further rationale for initiation of clinical studies with combinations of cytotoxic and molecularly targeted therapies for the treatment of bone cancer. In addition, imaging biomarkers for early assessment of treatment response will be evaluated and validated leading to individualization of treatment for bone cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Biomarkers Study Section (CBSS)
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Menkens, Anne E
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Nyati, Shyam; Chator, Areeb; Schinske, Katerina et al. (2016) A Requirement for ZAK Kinase Activity in Canonical TGF-? Signaling. Transl Oncol 9:473-481
Nyati, Shyam; Schinske-Sebolt, Katrina; Pitchiaya, Sethuramasundaram et al. (2015) The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-? signaling. Sci Signal 8:ra1
Hoff, Benjamin A; Toole, Michael; Yablon, Corrie et al. (2015) Potential for Early Fracture Risk Assessment in Patients with Metastatic Bone Disease using Parametric Response Mapping of CT Images. Tomography 1:98-104
Brisset, Jean-Christophe; Hoff, Benjamin A; Chenevert, Thomas L et al. (2015) Integrated multimodal imaging of dynamic bone-tumor alterations associated with metastatic prostate cancer. PLoS One 10:e0123877
Boes, Jennifer L; Hoff, Benjamin A; Hylton, Nola et al. (2014) Image registration for quantitative parametric response mapping of cancer treatment response. Transl Oncol 7:101-10
Chenevert, Thomas L; Malyarenko, Dariya I; Newitt, David et al. (2014) Errors in Quantitative Image Analysis due to Platform-Dependent Image Scaling. Transl Oncol 7:65-71
Lemasson, Benjamin; Galbán, Craig J; Boes, Jennifer L et al. (2013) Diffusion-Weighted MRI as a Biomarker of Tumor Radiation Treatment Response Heterogeneity: A Comparative Study of Whole-Volume Histogram Analysis versus Voxel-Based Functional Diffusion Map Analysis. Transl Oncol 6:554-61
Malyarenko, Dariya; Galbán, Craig J; Londy, Frank J et al. (2013) Multi-system repeatability and reproducibility of apparent diffusion coefficient measurement using an ice-water phantom. J Magn Reson Imaging 37:1238-46
Galbán, Stefanie; Jeon, Yong Hyun; Bowman, Brittany M et al. (2013) Imaging proteolytic activity in live cells and animal models. PLoS One 8:e66248
Hoff, Benjamin A; Kozloff, Kenneth M; Boes, Jennifer L et al. (2012) Parametric response mapping of CT images provides early detection of local bone loss in a rat model of osteoporosis. Bone 51:78-84

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