Death Receptors in Bladder Cancer Therapy

干扰素和其他免疫调节剂(即卡介苗)被用作膀胱患者的一线治疗 但他们的行动机制仍不清楚。干扰素具有强大的抗血管生成作用， 似乎有助于它们的抗肿瘤活性。此外，在我们的实验室进行的研究中 在孢子资助的第一个周期中，我们证明了干扰素-a(IFNA)诱导了一个亚群的细胞凋亡 (6/20)人膀胱癌细胞株及其诱导的肿瘤坏死因子表达 细胞凋亡诱导配体(TRAIL)的表达。在平行研究中，我们证明了一些膀胱 癌细胞对干扰素具有抗药性，因为它们对TRAIL具有抗药性。重要的是，我们证明了抵抗力 通过与蛋白酶体抑制剂Bortezomib(PS-341， VELCADE)或组蛋白脱乙酰酶抑制剂SANA，我们的初步数据有力地表明它们确实存在 因此，通过促进细胞周期蛋白依赖性激酶抑制物p21WAF-1/Cip-1的非依赖于P53的积聚。 在这次竞争性更新中提出的研究的总体目标是使用这些信息来设计 以死亡受体为基础的治疗尿路上皮癌的有效策略。为此，我们 提出以下3个具体目标。(1)确定p21在bortezomib或saha介导中的作用 尿路上皮癌细胞对干扰素或TRAIL的增敏作用。(2)评价TRAIL-OR的疗效和毒性。 以干扰素为基础的联合治疗活体原位膀胱肿瘤。(3)发展测量方法 患者对以硼替佐米为基础的治疗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，在这些项目中， 目前正在探索增强TRAIL敏感性和/或完全绕过TRAIL通路的策略。 这个项目与以前的生物制剂工作最重要的区别是它 细胞抑制剂似乎促进TRAIL诱导的肿瘤细胞凋亡，而它们可以 削弱许多(如果不是大多数)常规化疗药物的效果。所有的化合物 正在进行的研究要么已经获得FDA批准用于癌症治疗，要么正在进行 在L期临床试验中进行评估。因此，这个项目的一个重要特点就是我们将开设一个 我们最有希望的组合在孢子资助的第四年进行临床试验。

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.