Targeting Fas Inhibitors in Cancer Therapy

描述（由申请人提供）：由于对死亡受体（如Fas/CD 95/Apo-1）介导的细胞凋亡阻断机制的了解有限，阻碍了癌症治疗的进展。令人惊讶的是，尽管Fas受体在癌症中的普遍性和在癌症治疗中可能的有益作用，但很少有针对恢复Fas受体的研究。恢复癌细胞的Fas凋亡将是癌症治疗的重大突破。我们筛选了非霍奇金淋巴瘤（NHL）细胞的Fas抑制剂，并确定CD 74作为候选者。CD 74是一种主要组织相容性复合物相关蛋白，在造血系统癌症中高度表达。我们发现，CD 74结合Fas和抑制Fas介导的细胞凋亡。我们还发现，人慢性淋巴细胞白血病（CLL）和NHL肿瘤组织中含有CD 74-Fas复合物。我们用竞争性肽和抗CD 74抗体破坏了CD 74- Fas复合物，这大大促进了Fas介导的凋亡。在一项临床试验中，我们发现抗CD 74抗体治疗与CD 74-Fas复合物的破坏有关。因此，我们假设，CD 74-Fas复合物抑制细胞凋亡，并可以在体内被破坏，以增强细胞凋亡。在使用抗CD 74抗体治疗CLL和NHL患者的临床试验中，我们将CD 74抗体治疗与细胞凋亡和CD 74依赖性信号传导的细胞间介质相关联。我们还将分析化疗前和化疗期间血浆中的细胞间CD 74-Fas相关信号标志物。我们将确定CD 74靶向治疗抗肿瘤反应中激活的主要细胞内信号传导途径。作为替代方案，我们将分析来自患者的CLL细胞中的CD 74-Fas信号传导，所述CLL细胞在用氟达拉滨、环磷酰胺、利妥昔单抗治疗之前和期间，其在肿瘤消退中使用Fas介导的凋亡。该项目的长期目标是详细了解Fas抑制剂可以调节以增强癌细胞凋亡的机制。 公共卫生相关性：淋巴瘤和白血病表达Fas，但通常对Fas介导的细胞凋亡有抵抗力。我们已经确定了Fas的抑制剂，称为CD 74，并将治疗患者的抗CD 74抗体。我们将通过检测CD 74依赖性信号传导和凋亡率来确定CD 74抗体是否在体内使癌细胞对凋亡敏感。

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.