Targeting Fas Inhibitors in Cancer Therapy

描述(由申请人提供)：由于对Fas/CD95/Apo-1等死亡受体介导的阻止细胞凋亡的机制了解有限，癌症治疗的进展一直受到阻碍。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，但几乎没有针对恢复Fas受体的研究。恢复癌细胞Fas的凋亡将是癌症治疗的重大突破。我们对非霍奇金淋巴瘤(NHL)细胞进行了Fas抑制物筛选，并确定CD74为候选细胞。CD74是一种主要的组织相容性复合体相关蛋白，在血液系统肿瘤中高表达。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NHL肿瘤组织中含有CD74-Fas复合体。我们用相互竞争的多肽和抗CD74抗体破坏了CD74-Fas复合体，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抗体治疗与破坏CD74-Fas复合体有关。因此，我们假设CD74-Fas复合体抑制细胞凋亡，并可在体内被破坏以促进细胞凋亡。在使用抗CD74抗体治疗CLL和NHL患者的临床试验中，我们将CD74抗体治疗与细胞间凋亡介质和CD74依赖的信号转导联系起来。我们还将在化疗前和化疗期间分析血浆中细胞间CD74-Fas相关信号标志物。我们将确定CD74靶向治疗在抗肿瘤反应中激活的主要细胞内信号通路。作为替代方案，我们将在氟达拉滨、环磷酰胺和利妥昔单抗治疗前和治疗期间分析患者CLL细胞中CD74-Fas信号，利妥昔单抗在肿瘤消退中使用Fas介导的细胞凋亡。该项目的长期目标是详细了解Fas抑制物可被调节以促进癌细胞凋亡的机制。 公共卫生相关性：淋巴瘤和白血病表达Fas，但通常对Fas介导的细胞凋亡具有抵抗力。我们已经确定了一种Fas的抑制剂，称为CD74，并将用抗CD74抗体治疗患者。我们将通过检测CD74依赖的信号和凋亡率来确定CD74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.