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 #
5P50CA058236-16
Application #
8116705
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
16
Fiscal Year
2010
Total Cost
$246,016
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Karnes, R Jeffrey; Choeurng, Voleak; Ross, Ashley E et al. (2018) Validation of a Genomic Risk Classifier to Predict Prostate Cancer-specific Mortality in Men with Adverse Pathologic Features. Eur Urol 73:168-175
Menezes, Mitchell E; Bhoopathi, Praveen; Pradhan, Anjan K et al. (2018) Role of MDA-7/IL-24 a Multifunction Protein in Human Diseases. Adv Cancer Res 138:143-182
Jiang, Wen; Ulmert, David; Simons, Brian W et al. (2018) The impact of age on radium-223 distribution and an evaluation of molecular imaging surrogates. Nucl Med Biol 62-63:1-8
Tsang, Sabrina H; Peisch, Samuel F; Rowan, Brendan et al. (2018) Association between Trichomonas vaginalis and prostate cancer mortality. Int J Cancer :
Baena-Del Valle, Javier A; Zheng, Qizhi; Esopi, David M et al. (2018) MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer. J Pathol 244:11-24
Martino, Thiago; Kudrolli, Tarana A; Kumar, Binod et al. (2018) The orally active pterocarpanquinone LQB-118 exhibits cytotoxicity in prostate cancer cell and tumor models through cellular redox stress. Prostate 78:140-151
Kaur, Harsimar B; Guedes, Liana B; Lu, Jiayun et al. (2018) Association of tumor-infiltrating T-cell density with molecular subtype, racial ancestry and clinical outcomes in prostate cancer. Mod Pathol 31:1539-1552
Zhu, Yezi; Sharp, Adam; Anderson, Courtney M et al. (2018) Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Eur Urol 73:727-735
Teply, Benjamin A; Wang, Hao; Luber, Brandon et al. (2018) Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol 19:76-86
Zennami, Kenji; Choi, Su Mi; Liao, Ross et al. (2018) PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance. Mol Cancer Res :

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