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.
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.
|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 :|
|Bhanvadia, Raj R; VanOpstall, Calvin; Brechka, Hannah et al. (2018) MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease. Clin Cancer Res 24:3668-3680|
|Antonarakis, Emmanuel S; Lu, Changxue; Luber, Brandon et al. (2018) Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. Eur Urol 74:218-225|
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