VEGF Function in B-CLL

VEGF 在 B-CLL 中的功能

• 批准号: 7098920
• 负责人: Neil E Kay
• 金额: $ 26.48万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098920
• 关键词: VEGF; Function; CLL

DESCRIPTION (provided by applicant): B-CLL represents a very common B cell malignancy without a curative approach. Given the aging of the North American population and the continued absence of a means to eradicate this disease, the management remains very difficult. Thus, novel insights into the biology of B-CLL are essential if we are to make progress. Angiogenesis in B-CLL is increasingly implicated as relevant to the biology of the disease process. For example we have found that the neovascularization found in CLL marrow increases as the disease stage progresses and that a VEGF based autocrine pathway induces increases in CLL B cell leukemic apoptotic resistance. This latter aspect we feel is crucial as the biologic hallmark of CLL B cells are their resistance to cell death or apoptosis. The CLL B cell elaborates VEGF that is able to bind to CLL B cell VEGFR-1 and VEGF-R2 type receptors with subsequent enhancement of the leukemic CLL B cell apoptosis resistance. We have gained some insight into the relevant downstream signaling molecules in particular that STAT3 activation and translocation into the CLL nucleus occurs with exposure of CLL B cells to VEGF. In addition, we have found that agents which interrupt the VEGF autocrine pathway, such as Bevacizumab (Avastin) can result in increased CLL B cell killing. In addition we now know that HIF1a a key transcription factor for VEGF is consistently overexpressed in CLL B cells. We have yet to understand the relative importance of each VEGF receptor in signaling and why other mediator molecules such as HIF1a are elevated in CLL B cells. We propose that with further analysis of the role of the VEGF membrane receptors in signaling of CLL B cells, understanding why HIF1a is elevated in these cells and determining what signaling events are critical to CLL B cell apoptosis resistance that we will have important biologic information that will allow us to exploit these findings for therapeutic purposes. Finally, if the administration of Bevacizumab in a clinical trial setting can result in reduction in leukemic CLL B cell levels of relapsed/refractory B-CLL patients and/or generate clinical responses (see appendix 1 for clinical trial) we will validate that a VEGF based pathway is highly relevant to B-CLL progression. Our specific aims in this proposal are: 1) Evaluate the impact and mechanism by which the angiogenic factor, VEGF when secreted by CLL B cells, alters CLL B cell apoptosis and drug resistance. 2) To determine the mechanism for increased production of VEGF in B-CLL B cells cultured under normoxic and hypoxic conditions. 3) Does the VEGF/VEGF-R pathway(s) found in CLL B cells correlate with either clinical and/or critical biologic parameters in B-CLL?

描述（由申请人提供）：B-CLL代表一个非常常见的B细胞恶性肿瘤，没有治愈方法。鉴于北美人口的老龄化以及继续缺乏消除这种疾病的手段，管理层仍然非常困难。因此，如果我们要取得进步，对B-CLL生物学的新颖见解至关重要。 B-CLL中的血管生成与疾病过程的生物学有关。例如，我们发现，随着疾病阶段的发展，CLL骨髓中发现的新血管化增加，并且基于VEGF的自分泌途径会诱导CLL B细胞白血病凋亡抗性的增加。我们认为后一个方面至关重要，因为CLL B细胞的生物学标志是它们对细胞死亡或凋亡的抗性。 CLL B细胞阐述了能够与Cll B细胞VEGFR-1和VEGF-R2型受体结合的VEGF，随后增强了白血病CLL B细胞凋亡耐药性。我们已经深入了解了相关的下游信号分子，特别是，随着CLL B细胞暴露于VEGF，STAT3激活和转移到CLL核中发生。此外，我们发现中断VEGF自分泌途径（例如贝伐单抗（avastin））的药物会导致CLL B细胞杀死增加。此外，我们现在知道HIF1A在CLL B细胞中始终过表达VEGF的关键转录因子。我们尚未了解每个VEGF受体在信号传导中的相对重要性，以及为什么其他介体分子（例如HIF1A）在CLL B细胞中升高。我们建议，通过进一步分析VEGF膜受体在CLL B细胞信号传导中的作用，了解为什么在这些细胞中升高HIF1A并确定哪些信号事件对于CLL B细胞凋亡耐药性至关重要，我们将具有重要的生物学信息，这将使我们能够利用这些发现来利用这些发现来获得治疗目的。最后，如果在临床试验环境中给予贝伐单抗可能会导致复发/难治性B-CLL患者的白血病CLL B细胞水平降低和/或产生临床反应（请参阅附录1有关临床试验），我们将验证基于VEGF的途径与B-CLL的途径非常相关。我们在该提案中的具体目的是：1）评估CLL B细胞分泌的血管生成因子（VEGF）的影响和机制，改变了CLL B细胞凋亡和耐药性。 2）确定在常氧和低氧条件下培养的B-CLL B细胞中VEGF产生的机制。 3）CLL B细胞中发现的VEGF/VEGF-R途径是否与B-CLL中的临床和/或关键生物学参数相关？