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

基本信息

批准号：
7345652
负责人：
Ajay Gopal
金额：
$ 27.24万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7345652
关键词：
Adverse effects All-Trans-Retinol Antibody Therapy Apoptosis Apoptotic B-Cell NonHodgkins Lymphoma B-Lymphocytes Biological Products Cancer Etiology Cell Death Cessation of life Clinical Clinical Data Clinical Trials Daily Data Diagnosis Disease remission Dose Dose-Limiting Drug Kinetics Drug resistance Exhibits Fenretinide Future In Vitro Induction of Apoptosis Lead Lymphoma MS4A1 gene Malignant - descriptor Malignant Neoplasms Marrow Measures Methods Mitochondria Modality Monoclonal Antibody CD20 Non-Hodgkin&apos s Lymphoma Normal tissue morphology Numbers Oncogenic Oral Partial Remission Pathway interactions Patients Personal Satisfaction Pharmaceutical Preparations Phase Phase III Clinical Trials Pilot Projects Plasma Positron Proliferation Marker Protein Overexpression Radiation therapy Randomized Rate Research Proposals Resistance Retinoids Safety Signal Transduction Staging Testing Thinking Time Tissues Toxic effect Treatment Protocols United States Vitamin A Week absorption base chemotherapeutic agent clinical efficacy day improved in vivo innovation neoplastic cell novel partial response pre-clinical resistance factors response rituximab success therapy development tositumomab tumor tumor progression

项目摘要

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例非霍奇金淋巴瘤（NHL）的新病例，这是癌症死亡的第五大最常见原因。 NHL中主要的致癌异常之一是其对凋亡的固有耐药性，最终导致耐药性和肿瘤进展。直到最近，大多数NHL治疗方法都试图通过传统的化学治疗剂或放射治疗来克服凋亡的抗性，但是这些方式对正常组织和肿瘤细胞产生了不利影响。相反，抗CD20单克隆抗体（MOAB），例如利妥昔单抗优先针对正常和恶性B细胞，并通过包括细胞凋亡在内的多种机制诱导细胞死亡。不幸的是，仅对利妥昔单抗的大多数临床反应都是部分的，缓解持续时间通常不到1年。在不增加毒性的情况下提高抗CD20摩ab的疗效的尝试取得了有限的成功。我们的临床前数据表明，一种无毒的口服促凋亡类视黄素的芬列汀表现出很大的单药活性，并且可以显着增强抗CD20摩押的抗肿瘤作用。这项研究建议的目的是进行新的L/LL临床试验，该试验评估了芬雷丁素对抗CD20抗体治疗的反应的能力，而不会引起显着的其他额外毒性。在AIM 1中，我们将使用传统的反应措施以及正电子发射断层造影反应评估B-NHL患者中单独的芬雷丁苷和与利妥昔单抗的临床活性。 AIM 2将评估烯醇和视黄醇的血浆，骨髓和肿瘤药代动力学，并将这些发现与剂量限制毒性和临床反应相关联。 AIM 3将通过评估增殖，凋亡耐药性和离体凋亡 - 诱导措施来确定临床反应的肿瘤特异性预测指标，并阐明体内作用机理。该项目的结果对于这种疗法的未来发展至关重要，并有可能导致一种新颖，实用，廉价，耐受性，口服方法来优化抗CD20治疗对B-NHL的功效。