Outcomes for patients with high risk localized prostate cancer treated with standard radiotherapy and androgen ablation are unacceptable. The addition of radiation sensitizing agents to radiotherapy is useful in other locally advanced cancers such lung and rectal cancer. TNF-alpha is a potent radiosensitizing antitumor agent, but toxicity limits its use as a systemic drug. Ad.Egr-TNF.11D (TNFeradeTM, GenVec, Gaithersburg, MD) is a replication deficient E1, E3, E4 deleted adenoviral vector that encodes radio- inducible DNA sequences upstream from a cDNA for human TNF-alpha. Ad.Egr-TNF.11D is activated following radiation to produce intratumoral therapeutic levels of TNF-alpha and enhanced tumor regression via vascular destruction and thrombosis. To develop this concept clinically an early phase clinical trial of Ad.Egr-TNF.11D, radiotherapy, and androgen ablation to determine if the combination is safe in these patients will be conducted. It is recognized that addition of inducible local TNF is unlikely to be sufficient for this population and that additional measures need to be explored. Furthermore, markers for predicting whih patients are most likely to benefit need to be developed. In regards to the former, activation of NFkB by both TNF and radiation may be critical to promoting survival and inhibiting both the cancer and endothelial cell death required for successful treatment. Therefore, it will be determined if inhibition of NFkB activation through use of the triterpenoid CDDO or an adenoviral vector that inhibits NFkB by encoding a non-degradable (""""""""super- repressor"""""""") form of IKBa (Ad.CMV.IkBa) further enhances the activity of Ad.Egr-TNF.11D and radiotherapy in preclinical prostate cancer models. Finally, it has been demonstrated that STAT1 is induced by radiation and preliminary evidence suggests that upregulation of STAT1 predicts for resistance to irradiation, raising the hypothesis that patients with baseline elevated tumor STAT1 levels will respond less well to standard radiation. It will thus be determined if STAT1 and NFkB overexpression are associated with recurrence in a historical group of locally advanced prostate cancer patients with the prediction that the association will be stronger in patients treated with radiotherapy than in patients treated with surgery.

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Northwestern University at Chicago
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Hung, Michelle E; Lenzini, Stephen B; Stranford, Devin M et al. (2018) Enrichment of Extracellular Vesicle Subpopulations Via Affinity Chromatography. Methods Mol Biol 1740:109-124
Weiner, Adam B; Tsai, Kyle P; Keeter, Mary-Kate et al. (2018) The Influence of Decision Aids on Prostate Cancer Screening Preferences: A Randomized Survey Study. J Urol 200:1048-1055
Nettey, Oluwarotimi S; Walker, Austin J; Keeter, Mary Kate et al. (2018) Self-reported Black race predicts significant prostate cancer independent of clinical setting and clinical and socioeconomic risk factors. Urol Oncol 36:501.e1-501.e8
Xu, Li; Gordon, Ryan; Farmer, Rebecca et al. (2018) Precision therapeutic targeting of human cancer cell motility. Nat Commun 9:2454
Zhang, Qiang; Helfand, Brian T; Carneiro, Benedito A et al. (2018) Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-? Insensitive Genetically Targeted CD8+ T-cells Derived from Patients with Metastatic Castrate-resistant Disease. Eur Urol 73:648-652
Pascal, Laura E; Masoodi, Khalid Z; Liu, June et al. (2017) Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia. J Endocrinol 235:123-136
Dominguez, Donye; Ye, Cong; Geng, Zhe et al. (2017) Exogenous IL-33 Restores Dendritic Cell Activation and Maturation in Established Cancer. J Immunol 198:1365-1375
Murphy, A B; Nyame, Y A; Batai, K et al. (2017) Does prostate volume correlate with vitamin D deficiency among men undergoing prostate biopsy? Prostate Cancer Prostatic Dis 20:55-60
Loeb, Stacy; Shin, Sanghyuk S; Broyles, Dennis L et al. (2017) Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer. BJU Int 120:61-68
Zhang, Minghui; Dominguez, Donye; Chen, Siqi et al. (2017) WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability. Oncol Lett 14:3580-3586

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