VEGF Function in B-CLL

描述（由申请人提供）：B-CLL代表一种非常常见的B细胞恶性肿瘤，无治愈方法。鉴于北美人口老龄化和持续缺乏根除这种疾病的手段，管理仍然非常困难。因此，如果我们要取得进展，对B-CLL生物学的新见解至关重要。B-CLL中的血管生成越来越多地涉及疾病过程的生物学。例如，我们已经发现，在CLL骨髓中发现的新血管形成随着疾病阶段的进展而增加，并且基于VEGF的自分泌途径诱导CLL B细胞白血病凋亡抗性的增加。我们认为后一个方面是至关重要的，因为CLL B细胞的生物学标志是它们对细胞死亡或细胞凋亡的抗性。CLL B细胞产生VEGF，其能够结合CLL B细胞VEGFR-1和VEGF-R2型受体，随后增强白血病CLL B细胞凋亡抗性。我们已经对相关的下游信号分子有了一些了解，特别是当CLL B细胞暴露于VEGF时，STAT 3活化并易位到CLL细胞核中。此外，我们发现阻断VEGF自分泌途径的药物，如贝伐单抗（Avastin）可导致CLL B细胞杀伤增加。此外，我们现在知道HIF 1a是VEGF的关键转录因子，在CLL B细胞中持续过表达。我们还没有了解每个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如HIF 1a在CLL B细胞中升高。我们建议，进一步分析VEGF膜受体在CLL B细胞信号传导中的作用，了解HIF 1a在这些细胞中升高的原因，并确定哪些信号传导事件对CLL B细胞凋亡抗性至关重要，我们将获得重要的生物学信息，使我们能够利用这些发现用于治疗目的。最后，如果贝伐珠单抗在临床试验环境中给药可导致复发性/难治性B-CLL患者的白血病CLL B细胞水平降低和/或产生临床应答（临床试验见附录1），我们将验证基于VEGF的途径与B-CLL进展高度相关。我们的具体目标是：1）评估血管生成因子VEGF在CLL B细胞分泌时改变CLL B细胞凋亡和耐药性的影响和机制。2)探讨常氧和低氧条件下培养的B-CLL B细胞VEGF表达增加的机制。3)CLL B细胞中发现的VEGF/VEGF-R通路是否与B-CLL的临床和/或关键生物学参数相关？

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?