Proapoptotic Therapy for B-cell Non Hodgkin's Lymphoma

描述（由申请人提供）：美国每年诊断出近 60,000 例新发非霍奇金淋巴瘤 (NHL) 病例，它是癌症死亡的第五大常见原因。 NHL 的主要致癌异常之一是其固有的细胞凋亡抵抗力，这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化疗药物或放射治疗来克服细胞凋亡抵抗，但这些方式会对正常组织和肿瘤细胞产生不利影响。相比之下，抗 CD20 单克隆抗体 (MoAb)（例如利妥昔单抗）优先靶向正常和恶性 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，大多数单用利妥昔单抗的临床反应是部分反应，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 MoAb 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 胺是一种无毒的口服促凋亡类维生素A，具有显着的单药活性，可以显着增强抗 CD20 MoAb 的抗肿瘤作用。该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胺放大抗 CD20 抗体治疗反应而不产生显着额外毒性的能力。在目标 1 中，我们将使用传统反应测量以及正电子发射断层扫描反应来评估芬维A胺单独使用以及与利妥昔单抗联合使用对 B-NHL 患者的临床活性。目标 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毒性和临床反应相关联。目标 3 将确定临床反应的肿瘤特异性预测因子，并通过评估增殖标记物、细胞凋亡抗性和离体细胞凋亡诱导措施来阐明体内作用机制。该项目的结果对该疗法的未来发展至关重要，并有可能产生一种新颖、实用、廉价、耐受性良好的口服方法，以优化 B-NHL 抗 CD20 疗法的疗效。

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.