Proapoptotic Therapy for B-cell Non Hodgkin's Lymphoma

B 细胞非霍奇金淋巴瘤的促凋亡治疗

• 批准号: 7056286
• 负责人: Ajay Gopal
• 金额: $ 29.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056286
• 关键词: antineoplastics; apoptosis; clinical research; lymphoma; monoclonal antibody; neoplasm /cancer

DESCRIPTION (provided by applicant): Nearly 60,000 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed each year in the United States, and it is the fifth most common cause of cancer death. One of the major oncogenic abnormalities in NHL is its inherent resistance to apoptosis, which ultimately contributes to drug resistance and tumor progression. Until recently, most treatments for NHL have attempted to overcome apoptosis-resistance with traditional chemotherapeutic agents or radiation therapy, but these modalities adversely impact the normal tissues as well as tumor cells. In contrast, anti-CD20 monoclonal antibodies (MoAbs) such as rituximab preferentially target normal and malignant B-cells and induce cell death via a number of mechanisms including apoptosis. Unfortunately, most clinical responses to rituximab alone are partial and remission durations are typically less than 1 year. Attempts to improve the efficacy of anti-CD20 MoAbs without adding toxicity have met with limited success. Our pre-clinical data demonstrate that fenretinide, a non-toxic oral pro-apoptotic retinoid, exhibits substantial single-agent activity and can dramatically enhance the anti-tumor effect of anti-CD20 MoAbs. The objective of this research proposal is to conduct a novel phase l/ll clinical trial evaluating the ability of fenretinide to amplify responses to anti-CD20 antibody therapy without incurring significant additional toxicity. In Aim 1 we will assess the clinical activity of fenretinide alone and in combination with rituximab in patients with B-NHL using both traditional response measures as well as positron emission tomographic responses. Aim 2 will evaluate the plasma, marrow and tumor pharmacokinetics of fenretinide and retinol and correlate these findings with the dose limiting toxicities and clinical responses. Aim 3 will determine tumor-specific predictors of clinical response and elucidate the in vivo mechanisms of action by evaluating markers of proliferation, apoptosis-resistance and ex vivo apoptosis-induction measures. The results of this project will be critical to the future development of this therapy and potentially lead to a novel, practical, inexpensive, well-tolerated, oral method to optimize the efficacy of anti-CD20 therapy for B-NHL.

描述（由申请人提供）：在美国，每年诊断出近60，000例新的非霍奇金淋巴瘤（NHL）病例，它是癌症死亡的第五大常见原因。NHL中的主要致癌异常之一是其固有的对细胞凋亡的抗性，这最终导致耐药性和肿瘤进展。直到最近，NHL的大多数治疗都试图用传统的化疗剂或放射治疗来克服肿瘤耐药性，但这些方式对正常组织以及肿瘤细胞产生不利影响。相反，抗CD 20单克隆抗体（MoAb）如利妥昔单抗优先靶向正常和恶性B细胞，并通过多种机制（包括凋亡）诱导细胞死亡。不幸的是，大多数单独使用利妥昔单抗的临床反应都是部分的，缓解持续时间通常少于1年。在不增加毒性的情况下提高抗CD 20单克隆抗体的功效的尝试取得了有限的成功。我们的临床前数据表明，芬维A胺，一种无毒的口服促凋亡类维生素A，表现出相当大的单药活性，可以显着增强抗CD 20单克隆抗体的抗肿瘤作用。本研究计划的目的是进行一项新的I/II期临床试验，评估芬维A胺增强抗CD 20抗体治疗应答而不产生显著额外毒性的能力。在目的1中，我们将使用传统的反应测量以及正电子发射断层扫描反应来评估单独使用芬维A胺和与利妥昔单抗联合使用在B-NHL患者中的临床活性。目的2将评估芬维A胺和视黄醇的血浆、骨髓和肿瘤药代动力学，并将这些发现与剂量限制性毒性和临床反应相关联。目的3将确定临床反应的肿瘤特异性预测因子，并通过评价增殖、增殖抗性和离体增殖诱导指标来阐明体内作用机制。该项目的结果将对该疗法的未来发展至关重要，并可能导致一种新颖、实用、廉价、耐受性良好的口服方法，以优化抗CD 20治疗B-NHL的疗效。