Radiation is one of the key treatment choices for advanced prostate cancer (PCa), and radiation is an adjuvant treatment or alternative to surgery for organ-confined PCa. External beam radiation is associated with significant toxicities to the neighboring tissues. Combining radiation therapy with radiation sensitizers for PCa would permit lower doses of ionizing radiation with higher efficacy - this would both improve the therapeutic outcomes, and limit the common and debilitating side-effects of radiation. The objective of this application is to establish whether activation of transcription factor Stat5a/b determines the response of PCa to radiation therapy. We will test the following hypothesis: Active transcription factor Stat5a/b induces resistance of PCa cells to radiation therapy via promotion of double-strand DNA break repair. The rationale for this study is based on the applicants'previous findings demonstrating that: 1) Stat5a/b is critical for viability of Stat5a/b-positive PCa cell lies, for growth of human PCa xenograft tumors in nude mice and Stat5a/b promotes metastatic behavior of PCa cells in vitro and in vivo;2) Stat5 regulation of PCa cell viability is mediated through androgen receptor (AR)-dependent and AR-independent mechanisms, 3) Elevated nuclear Stat5a/b levels in PCa predict early disease recurrence and 45% increased likelihood of PCa-specific death;4) Nuclear Stat5a/b is over-expressed in castrate-resistant clinical PCas 5) Stat5a/b inhibition sensitizes PCa cells to radiation;6) Inhibition of Stat5a/b increases radiatio-induced DNA- damage in PCa cells and 7) Stat5a/b up-regulates Rad51 which is the key protein in Homologous Recombination (HR)-DNA repair in mammalian cells.
Specific aims :
Aim 1) Determine whether Stat5a/b promotes radiation- induced a) HR double-strand (ds)DNA break repair through up-regulation of Rad51 and/or b) NHEJ DNA repair in PCa cells. 2) Determine whether inhibition of Stat5a/b sensitizes human PCa cell lines and xenograft tumors to radiation-induced regression. We will also establish the specificity of Stat5-inhibition-induced radiosensitization to PCa vs. normal surrounding tissues. 3) Establish whether elevated Stat5a/b levels in clinical human PCas predicts poor therapeutic response to radiation therapy. Innovation: The concept of Stat5a/b regulation of Rad51 and dsDNA break repair in PCa is entirely novel. Also, the concept of Stat5a/b inhibition as a strategy to sensitize human PCa to radiation is completely unexplored. The concept of active nuclear Stat5a/b as a predictive marker of PCas with poor response to radiation therapy is new. The proposed studies include unique PCa material from patients and unique research tools. Significance: The proposed studies hold the potential to identify a new strategy for sensitizing human PCa cells to radiation based on inhibition of Stat5a/b. This is important since development of a pharmacological radiation sensitizer for PCa would enable more effective destruction of the cancer cells and reduce the radiation therapy-related side-effects. The proposed work has direct significance for therapy development for PCa since existing small-molecule Jak2-Stat5 inhibitors could become immediately available to prostate cancer patients as pharmacological tools for radiation sensitization.
The objective of this proposal is to explore the therapy-relevant and novel concept that inhibition of Stat5a/b will sensitize human prostate cancer (PCa) to radiation, and thereby improve clinical outcome of patients as an adjuvant therapy. We will also determine if high levels of active nuclear Stat5a/b in clinical PCas predict poor response to radiation therapy. The project is important since Stat5a/b inhibition may provide a strategy to improve the therapeutic response of clinical PCa to radiation.
|Hoang, David T; Iczkowski, Kenneth A; Kilari, Deepak et al. (2017) Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles. Oncotarget 8:3724-3745|
|Liao, Zhiyong; Gu, Lei; Vergalli, Jenny et al. (2015) Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia. Mol Cancer Ther 14:1777-93|
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|Hoang, David T; Gu, Lei; Liao, Zhiyong et al. (2015) Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer. Mol Cancer Ther 14:713-26|
|Gu, Lei; Talati, Pooja; Vogiatzi, Paraskevi et al. (2014) Pharmacologic suppression of JAK1/2 by JAK1/2 inhibitor AZD1480 potently inhibits IL-6-induced experimental prostate cancer metastases formation. Mol Cancer Ther 13:1246-58|
|Gu, Lei; Liao, Zhiyong; Hoang, David T et al. (2013) Pharmacologic inhibition of Jak2-Stat5 signaling By Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer. Clin Cancer Res 19:5658-74|
|Mirtti, Tuomas; Leiby, Benjamin E; Abdulghani, Junaid et al. (2013) Nuclear Stat5a/b predicts early recurrence and prostate cancer-specific death in patients treated by radical prostatectomy. Hum Pathol 44:310-9|
|Haddad, Bassem R; Gu, Lei; Mirtti, Tuomas et al. (2013) STAT5A/B gene locus undergoes amplification during human prostate cancer progression. Am J Pathol 182:2264-75|
|Koptyra, Mateusz; Gupta, Shilpa; Talati, Pooja et al. (2011) Signal transducer and activator of transcription 5a/b: biomarker and therapeutic target in prostate and breast cancer. Int J Biochem Cell Biol 43:1417-21|
|Liao, Zhiyong; Lutz, Jacqueline; Nevalainen, Marja T (2010) Transcription factor Stat5a/b as a therapeutic target protein for prostate cancer. Int J Biochem Cell Biol 42:186-92|
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