Death Receptors in Bladder Cancer Therapy

膀胱癌治疗中的死亡受体

• 批准号: 7729506
• 负责人: David J. McConkey
• 金额: $ 18.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729506
• 关键词: Advanced Malignant Neoplasm; Antibodies; Apoptosis; Apoptotic; Biological Assay; Biological Markers; Biological Products; Bladder; Bladder Neoplasm; Blood; Bortezomib; Bypass; CDKN1A gene; Calmette-Guerin Bacillus; Cancer cell line; Caspase; Cell Death; Cell Line; Cells; Cessation of life; Chemicals; Clinical Trials; Clinical Trials[{..}] Cancer Treatment; Combined Modality Therapy; Complement; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Cystectomy; Cytostatics; Data; Defect; Disease; Dose; Doxorubicin/Gemcitabine; End Point; Enrollment; Event; Family; Funding; Future; Goals; Histones; Hour; Human; Human Genome; Immunomodulators; In Situ Nick-End Labeling; In Vitro; Incubated; Infection; Institution; Interferons; Invasive; Laboratories; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediating; Messenger RNA; Methods; Molecular; Muscle; Neoadjuvant Therapy; Normal tissue morphology; Nude Mice; Operative Surgical Procedures; Organ; PS341 cpd; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phosphotransferases; Primary Neoplasm; Process; Production; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Recombinants; Reproduction spores; Research; Residual Tumors; Resistance; Role; Sampling; Schedule; Science; Sentinel; Small Interfering RNA; Staining method; Stains; Standards of Weights and Measures; Surface; Systemic Therapy; TNFRSF10A gene; TNFRSF10B gene; TP53 gene; Testing; Therapeutic; Time; Tissues; Toxic effect; Transfection; Transitional Cell Carcinoma; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor Tissue; Tumor Volume; Unresectable; Up-Regulation; Urine; Velcade; Vorinostat; Week; Work; Xenograft procedure; base; cancer cell; cancer therapy; caspase-8; chemotherapeutic agent; cytokine; cytotoxic; design; gemcitabine; human TNF protein; in vivo; inhibitor/antagonist; killings; knock-down; multicatalytic endopeptidase complex; neoplastic cell; novel; oncoprotein p21; peripheral blood; preclinical study; receptor; receptor expression; research study; response; succinyl-trialanine-4-nitroanilide; tumor

Interferons and other immunomodulators (i.e. BCG) are used as front-line therapy in patients with bladder ancer, but their mechanisms of action remain unclear. Interferons have potent anti-angiogenic effects that appear to contribute to their anti-tumor activities. In addition, in studies performed by our laboratories during the first cycle of SPORE funding, we demonstrated that interferon-a (IFNa) induced apoptosis in a subset (6/20) of human bladder cancer cell lines and that IFNcc-induced expression of tumor necrosis factor apoptosis-inducing ligand (TRAIL) was involved. In parallel studies we demonstrated that some bladder cancer cells are IFN-resistant because they are resistant to TRAIL. Importantly, we showed that resistance to IFN or TRAIL could be reversed by incubating them with the proteasome inhibitor, bortezomib (PS-341, Velcade) or the histone deaceylase inhibitor, SANA, and our preliminary data strongly suggest that they do so by promoting the p53-independent accumulation of the cyclin-dependent kinase inhibitor, p21 Waf-1/Cip-1. The overall goal of the studies proposed in this competing renewal is to use this information to design an effective, death receptor-based therapeutic strategy for the treatment of urothelial cancer. To this end, we propose the following 3 Specific Aims. (1) Define the role of p21 in bortezomib- or SAHA-mediated sensitization of urothelial carcinoma cells to IFN or TRAIL. (2) Evaluate the efficacy and toxicity of TRAIL- or IFN-based combination therapies in orthotopic bladder tumors in vivo. (3) Develop methods to measure pharmacodynamic markers of biological response to bortezomib-based therapy in patients. These experiments will complement parallel studies being performed in Projects 4 and 5, where alternative strategies to enhance TRAIL sensitivity and/or bypass the TRAIL pathway altogether are being explored. The most important distinction between this project and previous work with biological agents is that it appears that cytostatic agents promote TRAIL-induced apoptosis in tumor cells, whereas they can undermine the effects of many (if not most) conventional chemotherapeutic agents. All of the compounds being studied are either already FDA-approved for the treatment of cancer or are in the process of being evaluated in Phase l-lll clinical trials. Therefore, an important feature of this project is that we will open a clinical trial of our most promising combination by the 4th year of SPORE funding.

干扰素和其他免疫调节剂（即卡介苗）用作膀胱患者的一线治疗 癌症，但其作用机制仍不清楚。干扰素具有强大的抗血管生成作用 似乎有助于其抗肿瘤活性。此外，在我们的实验室进行的研究中 在 SPORE 资助的第一个周期中，我们证明了干扰素-a (IFNa) 在一个亚群中诱导细胞凋亡 (6/20) 人膀胱癌细胞系和 IFNcc 诱导的肿瘤坏死因子表达 凋亡诱导配体（TRAIL）参与其中。在平行研究中，我们证明一些膀胱 癌细胞对 IFN 具有抗性，因为它们对 TRAIL 具有抗性。重要的是，我们证明了阻力 通过将它们与蛋白酶体抑制剂硼替佐米（PS-341， Velcade）或组蛋白脱乙酰酶抑制剂 SANA，我们的初步数据强烈表明它们确实 因此，通过促进细胞周期蛋白依赖性激酶抑制剂 p21 Waf-1/Cip-1 的不依赖于 p53 的积累。 此次竞争性更新中提出的研究的总体目标是利用这些信息来设计一个 有效的、基于死亡受体的治疗尿路上皮癌的治疗策略。为此，我们 提出以下 3 个具体目标。 (1) 定义p21在硼替佐米或SAHA介导中的作用 尿路上皮癌细胞对 IFN 或 TRAIL 的敏感性。 (2) 评估TRAIL-或的功效和毒性 基于 IFN 的体内原位膀胱肿瘤联合疗法。 (3) 制定衡量方法 患者对基于硼替佐米的治疗的生物反应的药效学标志物。这些 实验将补充项目 4 和 5 中正在进行的平行研究，其中替代方案 增强 TRAIL 敏感性和/或完全绕过 TRAIL 途径的策略正在探索中。 该项目与之前的生物制剂工作之间最重要的区别在于 细胞抑制剂似乎促进 TRAIL 诱导的肿瘤细胞凋亡，而它们可以 破坏许多（如果不是大多数）传统化疗药物的效果。所有化合物 正在研究的药物要么已经获得 FDA 批准用于治疗癌症，要么正在研究中 在 I-III 期临床试验中进行了评估。因此，这个项目的一个重要特点就是我们将开设一个 在 SPORE 资助的第四年，对我们最有前途的组合进行临床试验。