Targeting Fas Inhibitors in Cancer Therapy

描述（由申请人提供）：由于对Fas/CD95/Apo-1等死亡受体介导的细胞凋亡阻断机制的了解有限，癌症治疗的进展受到阻碍。令人惊讶的是，尽管Fas受体在癌症中普遍存在，并可能在癌症治疗中发挥有益作用，但很少有针对其恢复的研究。恢复fas细胞凋亡将是癌症治疗的重大突破。我们筛选非霍奇金淋巴瘤（NHL）细胞中的Fas抑制剂，并确定CD74作为候选。CD74是一种主要的组织相容性复合物相关蛋白，在造血肿瘤中高度表达。我们发现CD74结合Fas并抑制Fas介导的细胞凋亡。我们还发现人类慢性淋巴细胞白血病（CLL）和非hl肿瘤组织含有CD74-Fas复合物。我们用竞争肽和抗CD74抗体破坏了CD74- Fas复合物，这大大促进了Fas介导的细胞凋亡。在一项临床试验中，我们发现抗cd74抗体治疗与CD74-Fas复合物的破坏有关。因此，我们假设CD74-Fas复合物抑制细胞凋亡，并可被破坏以促进体内细胞凋亡。在一项使用抗CD74抗体治疗CLL和NHL患者的临床试验中，我们将把CD74抗体治疗与细胞间细胞凋亡介质和CD74依赖性信号传导联系起来。我们还将分析化疗前和化疗期间的血浆细胞间cd74 - fas相关信号标志物。我们将确定在cd74靶向治疗的抗肿瘤反应中激活的主要细胞内信号通路。作为一种替代方案，我们将分析患者在氟达拉滨、环磷酰胺、利妥昔单抗治疗前和治疗期间CLL细胞中的CD74-Fas信号，利用Fas介导的细胞凋亡促进肿瘤消退。该项目的长期目标是详细了解通过调节Fas抑制剂来增强癌细胞凋亡的机制。

DESCRIPTION (provided by applicant): Advances in cancer treatment have been hampered by a limited understanding of the mechanisms blocking apoptosis that is mediated by death receptors such as Fas/CD95/Apo-1. It is surprising that there is little research directed toward restoring Fas receptor, despite its pervasiveness in cancer and possible beneficial role in cancer therapy. Restoring Fas-apoptosis to cancer cells would be a major breakthrough in cancer therapy. We screened non-Hodgkin lymphoma (NHL) cells for inhibitors of Fas and identified CD74 as a candidate. CD74 is a major histocompatibility complex-associated protein that is highly expressed in hematopoietic cancers. We showed that CD74 binds Fas and suppresses Fas-mediated apoptosis. We also showed that human chronic lymphocytic leukemia (CLL) and NHL tumor tissues contain complexes of CD74-Fas. We disrupted the CD74- Fas complex with competing peptides and with an anti-CD74 antibody, which substantially facilitated Fas- mediated apoptosis. In a clinical trial we show anti-CD74 antibody therapy is associated with disruption of CD74-Fas complexes. We therefore hypothesize that CD74-Fas complexes inhibit apoptosis and can be disrupted to enhance apoptosis in vivo. In a clinical trial using anti-CD74 antibody for patients with CLL and NHL, we will correlate CD74 antibody therapy with intercellular mediators of apoptosis and CD74-dependent signaling. We will also analyze plasma before and during chemotherapy for intercellular CD74-Fas-related signaling markers. We will identify the predominant intracellular signaling pathway activated in antitumor responses with CD74-targeted therapy. As an alternative plan, we will analyze CD74-Fas signaling in CLL cells from patients before and during therapy with fludarabine, cyclophosphamide, rituximab, which uses Fas- mediated apoptosis in tumor regression. The long-term goal of this project is to develop a detailed understanding of mechanisms by which inhibitors of Fas can be modulated to enhance cancer cell apoptosis. PUBLIC HEALTH RELEVANCE: Lymphoma and leukemia express Fas but are commonly resistant to Fas-mediated apoptosis. We have identified an inhibitor of Fas, termed CD74, and will treat patients with the anti-CD74 antibody. We will determine if CD74 antibodies sensitize cancer cells to apoptosis in vivo by examining CD74-dependent signaling and apoptosis rates.