Developing novel diagnostic and therapeutic strategy to manage metastasis is a pressing issue in cancer research. The presence of lymph node metastases is a poor prognostic indicator. We have developed the adenoviral test vector, AdTSTA-sr39tk, which is designed to express the herpes simplex thymidine kinase (sr39tk) gene under the control of a highly amplified prostate-specific PSA promoter system (TSTA). The sr39tk gene has the capacity to produce positron emitting tomography (PET) signal and induce toxicity to cancer cells. Adenoviral vectors are frequently taken up into the lymphatics and transported to regional lymph nodes. A main objective of this study is to evaluate whether the prostate-specific AdTSTA-sr39tk PET imaging reporter vector can detect disseminated prostate cancer cells in the regional lymph nodes. The hypothesis is that if prostate cancer cells have disseminated to the same lymph node as the viral vector, then gene transfer and expression in the cancer cells mediated by AdTSTA-sr39tk will produce a PET signal in the lymph node after the administration of the [18F]-FHBG radiotracer substrate. Due to the cell-restricted expression control in the vector, a positive PET signal would indicate that AdTSTA-sr39tk gene transfer has occurred in prostate cancer cells. The tumoral lymphangiogenesis and lymphatic metastasis will be induced in the PTEN-null murine prostate cancer model. This model will in turn be used to test the vector-mediated PET diagnostic strategy to detect lymph node metastases. The second objective is to apply the AdTSTAsr39tk in a PET-guided therapeutic strategy to treat pet dogs that developed spontaneous prostate cancer. PET imaging after intratumoral injection of the viral vector will provide the location and magnitude of test gene expression prior to initiation of cytotoxic therapy. Testing of the novel prostate-targeted diagnostic and therapeutic strategy in relevant small and large animal model will be very helpful to guide the future clinical protocol for managing disseminated prostate cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA122693-01A1
Application #
7258636
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Menkens, Anne E
Project Start
2007-03-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
1
Fiscal Year
2007
Total Cost
$154,500
Indirect Cost
Name
University of California Los Angeles
Department
Urology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Pouliot, Frédéric; Sato, Makoto; Jiang, Ziyue Karen et al. (2013) A molecular imaging system based on both transcriptional and genomic amplification to detect prostate cancer cells in vivo. Mol Ther 21:554-60
Pouliot, Frédéric; Karanikolas, Breanne D W; Johnson, Mai et al. (2011) In vivo imaging of intraprostatic-specific gene transcription by PET. J Nucl Med 52:784-91
Jiang, Ziyue Karen; Sato, Makoto; Wei, Liu H et al. (2011) Androgen-independent molecular imaging vectors to detect castration-resistant and metastatic prostate cancer. Cancer Res 71:6250-60
Johnson, Mai; Karanikolas, Breanne D W; Priceman, Saul J et al. (2009) Titration of variant HSV1-tk gene expression to determine the sensitivity of 18F-FHBG PET imaging in a prostate tumor. J Nucl Med 50:757-64
Pouliot, Frédéric; Johnson, Mai; Wu, Lily (2009) Non-invasive molecular imaging of prostate cancer lymph node metastasis. Trends Mol Med 15:254-62
Huyn, Steven T; Burton, Jeremy B; Sato, Makoto et al. (2009) A potent, imaging adenoviral vector driven by the cancer-selective mucin-1 promoter that targets breast cancer metastasis. Clin Cancer Res 15:3126-34
Sato, M; Figueiredo, M L; Burton, J B et al. (2008) Configurations of a two-tiered amplified gene expression system in adenoviral vectors designed to improve the specificity of in vivo prostate cancer imaging. Gene Ther 15:583-93
Burton, Jeremy B; Priceman, Saul J; Sung, James L et al. (2008) Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res 68:7828-37
Burton, Jeremy B; Johnson, Mai; Sato, Makoto et al. (2008) Adenovirus-mediated gene expression imaging to directly detect sentinel lymph node metastasis of prostate cancer. Nat Med 14:882-8