Targeting Fas Inhibitors in Cancer Therapy

癌症治疗中的靶向 Fas 抑制剂

• 批准号: 7994053
• 负责人: FELIPE SAMANIEGO
• 金额: $ 20.62万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-14 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994053
• 关键词: Address; Antibodies; Antibody Therapy; Antitumor Response; Apoptosis; Apoptotic; Binding; Biological Assay; Blood; CD95 Antigens; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Clinical Trials; Complex; Cyclophosphamide; Functional disorder; Goals; Hematologic Neoplasms; Hepatocyte Growth Factor; Human; Interleukin-8; Ligands; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Mediator of activation protein; Migration Inhibitory Factor; Non-Hodgkin' s Lymphoma; Pathway interactions; Patients; Peptides; Plasma; Proteins; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; System; Tumor Necrosis Factor Ligand Superfamily Member 6; Tumor Tissue; apoptosis in lymphocytes; cancer cell; cancer therapy; chemotherapy; fludarabine; improved; in vivo; inhibitor/antagonist; leukemia/lymphoma; neoplastic cell; phenylpyruvate tautomerase; public health relevance; receptor; response; rituximab; tumor

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.

描述（由申请人提供）：癌症治疗的进展受到了对阻断由FAS/CD95/APO-1等死亡受体介导的凋亡机制的有限理解的阻碍。令人惊讶的是，尽管它在癌症中普遍存在，并且在癌症治疗中可能有益作用，但几乎没有针对恢复FAS受体的研究。恢复FAS凋亡对癌细胞将是癌症治疗的主要突破。我们筛选了非霍奇金淋巴瘤（NHL）细胞的FAS抑制剂，并将CD74鉴定为候选者。 CD74是一种主要的组织相容性复合物相关蛋白，在造血癌中高度表达。我们表明CD74结合FA并抑制FAS介导的凋亡。我们还表明，人类慢性淋巴细胞性白血病（CLL）和NHL肿瘤组织含有CD74-FAS的复合物。我们用竞争性肽和抗CD74抗体破坏了CD74-FAS复合物，该抗体基本上促进了FAS介导的细胞凋亡。在一项临床试验中，我们显示抗CD74抗体疗法与CD74-FAS复合物的破坏有关。因此，我们假设CD74-FAS复合物会抑制凋亡，并且可以破坏以增强体内凋亡。在使用抗CD74抗体的CLL和NHL患者的临床试验中，我们将将CD74抗体治疗与细胞凋亡的细胞间介质和CD74依赖性信号传导相关联。我们还将在化学疗法之前和期间分析与细胞间CD74-FAS相关信号标记的血浆。我们将通过CD74靶向治疗在抗肿瘤反应中鉴定出主要的细胞内信号传导途径。作为替代计划，我们将分析氟达拉滨，环磷酰胺，利妥昔单抗治疗前和治疗期间的CLL细胞中CD74-FAS信号传导，后者在肿瘤回归中使用FAS介导的凋亡。该项目的长期目标是对可以调节FAS抑制剂的机制进行详细的了解以增强癌细胞凋亡。 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抗性。我们已经确定了一种称为CD74的FAS抑制剂，并将治疗抗CD74抗体的患者。我们将通过检查CD74依赖性信号传导和凋亡速率来确定CD74抗体是否将癌细胞对体内细胞凋亡敏感。