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 i n 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? ? ? ?
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