Radiation therapy is one of two primary treatments for clinically-localized prostate cancer (PCa) and is the principal therapy for locally-advanced disease associated with a higher grade, stage and/or PSA. While the success rate for both radiation and surgery is high for low-grade organ-confined disease, the estimated ten year disease-free-survival for advanced disease is less than 50%. Therefore, a means to improve the therapeutic index for patients with clinically-localized high stage and/or grade prostate cancer would significantly decrease the morbidity and mortality of this disease. In this proposal, a model is described to test the hypothesis that the therapeutic index for local treatment of prostate cancer can be improved by selectively sensitizing prostatic cancer cells to ionizing radiation. Here, the natural pathways of genomic DNA damage repair will be the therapeutic target. Inherited mutations in these pathways, such as in Ataxia Telangiectasia, result in cellular hypersensitivity to ionizing radiation (IR). We have previously shown that mammalian cancer cells be made similarly hypersensitive to IR by knocking down DNA repair protein levels through RNA interference (RNAi) therapy. While promising, this strategy requires a means to selectively target prostatic cells. We now propose three specific aims to develop a model for selective radiation sensitization of prostate cancer cells through targeted RNAi therapy.
In Aim 1, we will determine the identity of additional novel gene targets in DNA repair pathways for enhanced radiation sensitization. Secondly, in Aim 2, we will develop an in vivo model for RNAi targeting and radiation sensitization through the use of a Prostate Specific Membrane Antigen (PSMA) targeting RNA aptamer developed in our laboratory. This aptamer, xPSM-AlO, has been previously applied to deliver RNAi therapeutics to prostate tumor cells in vivo. Lastly, in Aim 3, we will extend these pre-clinical studies to a phase I clinical trial to determine safety and selective target gene knock-down. These studies have great potential in developing the first tissue-selective radiation sensitization agent and in translating a novel strategy to decrease the morbidity and mortality of locally advanced prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
3P50CA058236-18S1
Application #
8719549
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
2013-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
18
Fiscal Year
2013
Total Cost
$152,068
Indirect Cost
$58,199
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ku, ShengYu; Lasorsa, Elena; Adelaiye, Remi et al. (2014) Inhibition of Hsp90 augments docetaxel therapy in castrate resistant prostate cancer. PLoS One 9:e103680
Regter, Sietze; Hedayati, Mohammad; Zhang, Yonggang et al. (2014) Androgen withdrawal fails to induce detectable tissue hypoxia in the rat prostate. Prostate 74:805-10
Bhatnagar, Akrita; Wang, Yuchuan; Mease, Ronnie C et al. (2014) AEG-1 promoter-mediated imaging of prostate cancer. Cancer Res 74:5772-81
Chalfin, Heather J; Frank, Steven M; Feng, Zhaoyong et al. (2014) Allogeneic versus autologous blood transfusion and survival after radical prostatectomy. Transfusion 54:2168-74
Brennen, W Nathaniel; Rosen, D Marc; Chaux, Alcides et al. (2014) Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer. Prostate 74:1308-19
Paller, C J; Olatoye, D; Xie, S et al. (2014) The effect of the frequency and duration of PSA measurement on PSA doubling time calculations in men with biochemically recurrent prostate cancer. Prostate Cancer Prostatic Dis 17:28-33
Durham, Nicholas M; Nirschl, Christopher J; Jackson, Christopher M et al. (2014) Lymphocyte Activation Gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS One 9:e109080
Gurel, Bora; Lucia, M Scott; Thompson Jr, Ian M et al. (2014) Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev 23:847-56
Lutz, Eric R; Wu, Annie A; Bigelow, Elaine et al. (2014) Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res 2:616-31
Zheng, Qizhi; Peskoe, Sarah B; Ribas, Judit et al. (2014) Investigation of miR-21, miR-141, and miR-221 expression levels in prostate adenocarcinoma for associated risk of recurrence after radical prostatectomy. Prostate 74:1655-62

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