Abstract 91: NF-κB as a prognostic marker and therapeutic target in prostate cancer

Abstract

Abstract NF-κB, a pleiotropic transcription factor, is broadly associated with oncogenesis through its ability to control cell proliferation and apoptosis. Aberrant NF-κB activation has been observed in various human malignancies including prostate cancer. Clinical studies demonstrate higher expression of p65/RelA, p50/RelB, and cRel in primary prostate cancer specimens and in metastatic tumors which correlate with poor survival. While NF-κB is considered to play a key role in prostate cancer progression, its value as prognostic marker and therapeutic target has not been elucidated. Through development of a new in vivo model and real-time imaging, we established the relevance of NF-κB as a biomarker and therapeutic target in prostate cancer. Crossbreeding of NF-κB-Luc Tag mice and TRAMP (transgenic adenocarcinoma mouse prostate) provide bi-transgenic offspring (LucTg/TRAMPTg mice) for the study. Noninvasive in vivo and ex vivo bioluminescence imaging for NF-κB activation, prostate cancer progression was followed for 40 weeks in these mice. Age-dependent cancer progression was observed in the prostate which positively correlated with NF-κB activation. Ex vivo analysis showed increased NF-κB activity in the dorsal-lateral prostate which was associated with tumor progression as evident by increase expression of proliferation marker, prostate weight and histologic analysis. For therapeutic relevance, 12 weeks old NF-κB-Luc Tag mice and bi-transgenic mice were gavaged with parthenolide (10 mg/kg), an NF-κB inhibitor for 5 days/week for 8 weeks. Whole body NF-κB activity was performed every 2 weeks, while ex-vivo NF-κB activity in the genitourinary complex, thymus, spleen, bladder and prostate gland was determined after 8 weeks. Other upstream and downstream NF-κB target proteins were determined by Western blotting in the dorsal-lateral prostate. Parthenolide treatment blocked NF-κB activity in the prostate; preserved gross anatomy, shape and size of the GU complex; and suppressed tumor progression as evident from decrease in p65/RelA, p50/RelB, PCNA and phosphorylation of IκBα in the dorso-lateral prostate. To analyze the role of NF-κB in metastasis, mice were subjected to surgical castration followed by measurement of NF-κB activity. Initial castration of mice exhibited decreased NF-κB activity in the prostate; whereas 67% of the castrated mice exhibited increase in NF-κB activity 2 weeks after castration which correlated with tumor recurrence and poor survival. Our findings for the first time demonstrate real-time NF-κB imaging in a pre-clinical model and establishes the relevance of NF-κB as a prognostic biomarker and potential therapeutic target in prostate cancer. Citation Format: Eugene Vykhovanets, Eswar Shankar, Sanjeev Shukla, Olena Vykhovanets, Gregory T. MacLennan, Sanjay Gupta. NF-κB as a prognostic marker and therapeutic target in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 91. doi:10.1158/1538-7445.AM2015-91