The long term objective of this project is to improve the therapeutic index of radiation therapy for the treatment of prostate cancer (PCa). Radiation therapy is one of two primary treatments for clinically-localized 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 treatment of patients with clinically-localized high stage and/or grade prostate cancer would significantly decrease the morbidity and mortality of this disease. To address this we developed prostate-targeted RNA interference (RNAi) agents that selectively inhibit DNA repair pathways in prostate cells. Tissue-specific targeting was achieved through an RNA aptamer, A10-3, which binds to the Prostate Specific Membrane Antigen (PSMA) on the cellular surface and is then internalized into cells. The conjugated short hairpin RNAs (shRNAs) are then processed by cellular RNAi machinery, leading to knockdown of specific DNA repair mRNA and proteins. In the previous funding cycle we demonstrated that these agents, when directly injected into the tumor, significantly enhance the therapeutic index of external beam radiation therapy. Here we propose to continue the development of this strategy by generating chemically synthesized aptamer-siRNA radiation sensitizing agents and evaluating their safety as intraprostatically injected agents in a Phase I clinical trial. In addition to this translational aim, we will perform pre-clinical studies to determine whether the aptamer-siRNA radiation sensitizing agents are effective following intravenous injection. If successful, this mode of administration would provide a secondary route for radio-sensitizing locally advanced PCa, it would provide a novel means to improve the efficacy of external beam radiation therapy for the management of bone pain, and finally it would provide a means to enhance the efficacy of systemically targeted radiotherapeutics.

Public Health Relevance

In summary, successful development and clinical translation of these approaches could have a great impact on the morbidity and mortality associated with locally advanced and advanced metastatic PCa by selectively enhancing the efficiency of radiation therapy within the tumor while not increasing damage to non-target tissues. The first clinical trial will determine the safety of administering these agents and will be a first-in-man tissue-specific radiation sensitization agent.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA058236-19A1
Application #
8739711
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
1997-09-30
Project End
2019-08-31
Budget Start
2014-09-25
Budget End
2015-08-31
Support Year
19
Fiscal Year
2014
Total Cost
$241,040
Indirect Cost
$92,250
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Guedes, Liana B; Morais, Carlos L; Almutairi, Fawaz et al. (2016) Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer. Clin Cancer Res 22:4651-63
Haffner, Michael C; Weier, Christopher; Xu, Meng Meng et al. (2016) Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. J Pathol 238:31-41
Barakat, David J; Mendonca, Janet; Barberi, Theresa et al. (2016) C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome-lysosome fusion. Cancer Lett 375:152-61
Murtola, Teemu J; Gurel, Bora; Umbehr, Martin et al. (2016) Inflammation in Benign Prostate Tissue and Prostate Cancer in the Finasteride Arm of the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 25:463-9
Jackson, Christopher M; Kochel, Christina M; Nirschl, Christopher J et al. (2016) Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination. Clin Cancer Res 22:1161-72
Hedayati, Mohammad; Haffner, Michael C; Coulter, Jonathan B et al. (2016) Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation. Clin Cancer Res 22:3310-9
Trock, Bruce J; Fedor, Helen; Gurel, Bora et al. (2016) PTEN loss and chromosome 8 alterations in Gleason grade 3 prostate cancer cores predicts the presence of un-sampled grade 4 tumor: implications for active surveillance. Mod Pathol 29:764-71
Wu, Jianguo; Ivanov, Andrei I; Fisher, Paul B et al. (2016) Polo-like kinase 1 induces epithelial-to-mesenchymal transition and promotes epithelial cell motility by activating CRAF/ERK signaling. Elife 5:
Levy, Oren; Brennen, W Nathaniel; Han, Edward et al. (2016) A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer. Biomaterials 91:140-50
Lotan, Tamara L; Wei, Wei; Morais, Carlos L et al. (2016) PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer. Eur Urol Focus 2:180-188

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