Radiation Inducible TNF-a Therapy for Prostate Cancer

点击翻译按钮获取中文摘要

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.