Proapoptotic Therapy for B-cell Non Hodgkin's Lymphoma

描述(申请人提供)：美国每年新增近6万例非霍奇金淋巴瘤(NHL)病例，是导致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对凋亡的抵抗，最终导致耐药和肿瘤进展。直到最近，大多数NHL的治疗都试图用传统的化疗药物或放射治疗来克服细胞凋亡抵抗，但这些方法对正常组织和肿瘤细胞都有不利的影响。相反，抗CD20的单抗(MoAbs)，如利妥昔单抗，优先靶向正常和恶性的B细胞，并通过包括凋亡在内的许多机制诱导细胞死亡。不幸的是，大多数单独对利妥昔单抗的临床反应是部分的，缓解期通常不到1年。在不增加毒性的情况下提高抗CD20 MoAbs的有效性的尝试取得了有限的成功。我们的临床前数据表明，非维甲酸是一种无毒的口服促细胞凋亡的维甲酸类化合物，具有显著的单药活性，并能显著增强抗CD20 MoAbs的抗肿瘤作用。这项研究计划的目的是进行一项L/11期新期临床试验，评估非维甲酸对抗CD20抗体治疗的放大反应而不会产生显著的额外毒性的能力。在目标1中，我们将使用传统的反应方法和正电子发射断层扫描反应来评估非维甲酸单药和联合利妥昔单抗在B-NHL患者中的临床活性。目的2评价非维甲酸和视黄醇在血浆、骨髓和肿瘤中的药代动力学，并将这些结果与剂量限制毒性和临床反应相关联。目的3将通过评估增殖、抗凋亡和体外诱导凋亡措施来确定临床反应的肿瘤特异性预测因子，并阐明其体内作用机制。该项目的结果将对该疗法的未来发展至关重要，并可能导致一种新的、实用的、廉价的、耐受性良好的口服方法来优化抗CD20治疗B-NHL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.