Death Receptors in Bladder Cancer Therapy

干扰素和其他免疫调节剂（即BCG）被用作膀胱癌患者的一线治疗 癌症，但其作用机制尚不清楚。干扰素具有有效的抗血管生成作用， 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基金的第一个周期中，我们证明了干扰素-a（IFNa）在一个子集中诱导细胞凋亡， （6/20）的人膀胱癌细胞系和IFN α诱导的肿瘤坏死因子表达 肿瘤坏死诱导配体（TRAIL）也参与其中。在平行研究中，我们证明了一些膀胱 癌细胞是IFN抗性的，因为它们对TRAIL有抗性。重要的是，我们发现 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如此 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p53非依赖性积累。 在这一竞争性更新中提出的研究的总体目标是利用这些信息设计一个 有效的，基于死亡受体的治疗策略，用于治疗尿路上皮癌。为此我们 提出以下三个具体目标。(1)定义p21在硼替佐米或SAHA介导的 尿路上皮癌细胞对IFN或TRAIL的敏感性。(2)评估TRAIL的疗效和毒性-或 基于IFN的联合治疗原位膀胱肿瘤的体内研究(3)制定衡量方法 在患者中对基于硼替佐米的治疗的生物学应答的药效学标志物。这些 实验将补充项目4和项目5中进行的平行研究， 正在探索增强TRAIL敏感性和/或完全绕过TRAIL途径的策略。 这个项目与以前的生物制剂工作最重要的区别在于， 细胞生长抑制剂似乎促进肿瘤细胞中TRAIL诱导的细胞凋亡，而它们可以 破坏了许多（如果不是大多数）常规化疗剂的效果。的所有化合物 正在研究的药物要么已经被FDA批准用于治疗癌症，要么正在研究中。 在I-III期临床试验中评估。因此，这个项目的一个重要特点是，我们将开设一个 我们最有前途的组合的临床试验的第四年的孢子资金。

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.