P-3: Radiation Inducible TNF-a Therapy for Prostate Cancer

P-3：前列腺癌的放射诱导 TNF-a 疗法

• 批准号: 8055506
• 负责人: RALPH R WEICHSELBAUM
• 金额: $ 30.02万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-31 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055506
• 关键词: Ablation; Adenovirus Vector; Androgens; Biological Markers; Blood Vessels; Cancer Model; Cancer Patient; Cell Death; Clinical; Clinical Trials; Complementary DNA; DNA Sequence; Data; Development; Dose; Endothelial Cells; External Beam Radiation Therapy; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Gleason Grade for Prostate Cancer; Goals; Head and neck structure; Human; Intensity-Modulated Radiotherapy; Local Therapy; Locally Advanced Malignant Neoplasm; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Methods; Molecular Profiling; NF-kappa B; Operative Surgical Procedures; Outcome; Patient Selection; Patients; Pelvis; Pharmaceutical Preparations; Phase; Phase I/II Trial; Phase II/III Trial; Population; Production; Prognostic Factor; Prostate; Prostate Cancer therapy; Prostatectomy; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radio; Rectal Cancer; Recurrence; Research Personnel; Resistance; STAT1 gene; Safety; Staging; Staining method; Stains; TNF gene; Testing; Therapeutic; Thrombosis; Toxic effect; Tumor Necrosis Factor-alpha; Up-Regulation; Xenograft Model; antitumor agent; cohort; design; disorder control; high risk; human TNF protein; improved; inhibitor/antagonist; irradiation; outcome forecast; overexpression; p65; pre-clinical; programs; radiation resistance; rectal; standard care; success; tumor; vector

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.

患有高风险局部前列腺癌患者的结局，该患者接受标准放疗和治疗 雄激素消融是不可接受的。辐射敏化剂对放射疗法的启发很有用 其他局部晚期癌症等肺癌和直肠癌。 TNF-Alpha是一种有效的放射敏化 抗肿瘤剂，但毒性限制了其用作系统性药物。 ad.Egr-tnf.11d（tnferadetm，genvec， 医学博士Gaithersburg是一个复制不足E1，E3，E4删除了编码无线电的腺病毒矢量 从cDNA上游的诱导DNA序列，用于人类TNF-α。 AD.EGR-TNF.11D被激活 辐射后产生肿瘤内治疗水平的TNF-α和增强的肿瘤回归 通过血管破坏和血栓形成。在临床上发展这一概念的早期临床试验 AD.EGR-TNF.11D，放疗和雄激素消融，以确定组合是否安全 将进行患者。 人们认识到，添加可诱导的局部TNF不可能足够 需要探索其他措施。此外，预测患者的标记很可能是 为了利益需要开发。关于前者，TNF和辐射激​​活NFKB 可能对促进生存和抑制癌症和内皮细胞死亡至关重要 成功的治疗。因此，将确定是否通过使用NFKB激活抑制 三萜CDDO或通过编码不可降解的NFKB抑制NFKB的腺病毒载体（“超级 - IKBA（ad.cmv.ikba）的抑制器”进一步增强了AD.EGR-TNF.11D和放射疗法的活性 在临床前前列腺癌模型中。 最后，已经证明STAT1是由辐射引起的，初步证据表明， STAT1的上调预测了对辐射的抵抗力，提出了基线患者的假设 升高的肿瘤STAT1水平对标准辐射的反应不太好。因此，如果STAT1，将确定 和NFKB的过表达与一组局部先进的前列腺的复发有关 癌症患者的预测是，接受放射治疗的患者会更强 比接受手术治疗的患者。