PSCA is a cell surface glycoprotein over-expressed in most localized prostate cancer and highly over- expressed in the great majority of prostate cancer bone metastases. Minibodies are antibody fragments with rapid tumor penetration and faster blood clearance than intact antibodies which allows I-124 labeled minibodies to be used as high contrast PET imaging agents. These studies seek to evaluate the ability of the anti-PSCA A11 minibody to address major unmet needs in the field of prostate cancer: non-invasive staging of prostate cancer and the evaluation of treatment response.
Aim 1 : Evaluate the sensitivity of I-124 labeled A11 minibody immunoPET for detecting models of prostate cancer metastasis and in vivo quantitation of PSCA expression. We will evaluate the sensitivity of the minibody to image small tumors and metastases in lymph node lung and bone and compare this sensitivity with conventional imaging techniques. We will also investigate both the minimum PSCA antigen density needed for A11 minibody immunoPET imaging and the quantitative relationship between A11 uptake and PSCA expression in a tumor.
Aim 2 : Evaluate the ability of A11 minibody immunoPET to track progression from HGPIN, to invasive adenocarcinoma, to metastases in transgenic mouse models. In this aim, we will use a transgenic prostate cancer mouse model to evaluate the ability of the A11 anti-PSCA minibody to image local prostate cancer, tumor invasion, and tumor metastasis in vivo.
Aim 3 : Evaluate the ability of A11 minibody immunoPET to non-invasively image tumor response to therapy. In this aim, we will measure changes in tumor cell surface expression of PSCA in response to therapy and evaluate the ability of A11 minibody immunoPET to measure these changes non-invasively as a means of monitoring therapeutic efficacy.

Public Health Relevance

The great challenges of treating prostate cancer are distinguishing between indolent cases and those that need to be treated aggressively and selecting an appropriate therapy for each patient's disease. This research will determine whether PET imaging using a radiolabeled anti-PSCA antibody fragment can image PSCA expression to distinguish between aggressive and indolent disease and predict if a chosen therapy is effective.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F09-D (08))
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Damico, Mark W
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Knowles, Scott M; Tavaré, Richard; Zettlitz, Kirstin A et al. (2014) Applications of immunoPET: using 124I-anti-PSCA A11 minibody for imaging disease progression and response to therapy in mouse xenograft models of prostate cancer. Clin Cancer Res 20:6367-78
Rochefort, Matthew M; Girgis, Mark D; Knowles, Scott M et al. (2014) A mutated anti-CA19-9 scFv-Fc for positron emission tomography of human pancreatic cancer xenografts. Mol Imaging Biol 16:721-9
Wilks, Moses Q; Knowles, Scott M; Wu, Anna M et al. (2014) Improved modeling of in vivo kinetics of slowly diffusing radiotracers for tumor imaging. J Nucl Med 55:1539-44
Tavaré, Richard; McCracken, Melissa N; Zettlitz, Kirstin A et al. (2014) Engineered antibody fragments for immuno-PET imaging of endogenous CD8+ T cells in vivo. Proc Natl Acad Sci U S A 111:1108-13
Knowles, Scott M; Zettlitz, Kirstin A; Tavaré, Richard et al. (2014) Quantitative immunoPET of prostate cancer xenografts with 89Zr- and 124I-labeled anti-PSCA A11 minibody. J Nucl Med 55:452-9
Choe, Uh-Joo; Rodriguez, April R; Lee, Brian S et al. (2013) Endocytosis and intracellular trafficking properties of transferrin-conjugated block copolypeptide vesicles. Biomacromolecules 14:1458-64
David, John M; Knowles, Scott; Lamkin, Donald M et al. (2013) Individually ventilated cages impose cold stress on laboratory mice: a source of systemic experimental variability. J Am Assoc Lab Anim Sci 52:738-44
Knowles, Scott M; Wu, Anna M (2012) Advances in immuno-positron emission tomography: antibodies for molecular imaging in oncology. J Clin Oncol 30:3884-92