CXCR4 regulation of tumor progression in Multiple Myeloma

描述（由申请方提供）：MM的特征是诊断时疾病广泛，存在多发性溶解性病变和骨髓（BM）播散性受累，这意味着MM的进展涉及外周血中MM细胞的连续循环和重新进入BM。 趋化因子在淋巴细胞运输和归巢中起核心作用，特别是趋化因子SDF-1及其受体CXCR 4沿着最近鉴定的受体CXCR 7。 我们推测，MM细胞驻留在其微环境中的能力的调节将改变其生物学特性并诱导对凋亡的敏感性。 具体目的1：确定MM细胞响应SDF-1/CXCR 4轴的归巢机制。 我们将通过以下方式测试这一目标：确定抑制MM的SDF-1依赖性归巢的长期生物学后遗症及其对肿瘤进展的影响，确定MM细胞与其他BM微环境细胞之间归巢动力学的差异，鉴定在体外和体内调节MM细胞响应CXCR 4和CXCR 7归巢的下游信号传导途径，以及这两种受体在MM中信号传导的差异，并确定其他趋化因子受体和粘附分子在归巢调节中的作用。 具体目标二：通过鉴定粘附于BM微环境的MM细胞与外周血中的MM细胞相比发生的生物学变化，鉴定SDF-1/CXCR 4与粘附分子即VLA-4和LFA-1的相互作用，以及鉴定CXCR 4/CXCR 7和/或粘附分子的抑制对MM细胞体内生长和存活的影响。 具体目标3：通过确定MM细胞对CXCR 4、CXCR 7、VLA-4和MMP 2/9抑制剂抑制的反应的生物学后遗症，确定MM细胞与其他骨髓细胞相比的动员动力学差异，以及确定与存在于BM中的恶性细胞相比，从BM中动员出来的MM细胞是否对细胞毒性剂引起的细胞凋亡更敏感。 靶向贩运将导致MM治疗方法的范式转变，我们将通过诱导外流和防止归巢和粘附来改变MM细胞驻留在其保护性骨髓微环境中的能力，从而增加对细胞凋亡的敏感性。 公共卫生相关性：骨髓瘤中肿瘤进展的机制尚不清楚。 我们将研究趋化因子SDF-1及其受体在调节骨髓瘤细胞进入骨髓、粘附和退出循环中的作用。 通过将骨髓瘤细胞从骨髓中动员出来来靶向这一过程将导致对细胞毒性剂杀死细胞的更高敏感性。

DESCRIPTION (provided by applicant): MM is characterized by widespread disease at diagnosis with the presence of multiple lytic lesions and disseminated involvement of the bone marrow (BM), implying that the progression of MM involves a continuous circulation of the MM cells in the peripheral blood and re-entrance into the BM. Chemokines play a central role in lymphocyte trafficking and homing, specifically the chemokine SDF-1, and its receptors, CXCR4 along with the recently identified receptor CXCR7. We hypothesize that modulation of the capacity of MM cells to reside in their microenvironment will change their biologic properties and induce sensitivity to apoptosis. Specific Aim 1: To identify mechanisms of homing of MM cells in response to the SDF-1/CXCR4 axis. We will test this aim by determining the long-term biological sequelae of inhibition of SDF-1-dependent homing of MM and its effect on tumor progression, determining the differences in kinetics of homing between MM cells and other BM microenvironment cells, identifying the downstream signaling pathways that regulate MM cells' homing in response to CXCR4 and CXCR7 in vitro and in vivo, and difference in signaling of these two receptors in MM, and identifying the role of other chemokine receptors and adhesion molecules in the regulation of homing. Specific Aim 2: To determine the in vitro and in vivo effects of the SDF-1/CXCR4 axis on adhesion and survival of MM cells by identifying the biological changes that occur in MM cells adherent to the BM microenvironment compared to those in the peripheral blood, identifying the interaction of SDF-1/CXCR4 with adhesion molecules namely VLA-4 and LFA-1, and identifying the effect of inhibition of CXCR4/CXCR7 and/or adhesion molecules on growth and survival of MM cells in vivo. Specific Aim 3: To identify mechanisms of egression/mobilization of MM cells in response to CXCR4/CXCR7 inhibition by determining the biological sequelae of mobilization of MM cells in response to inhibition of CXCR4, CXCR7, VLA-4 and MMP2/9 inhibitors, determining the difference in kinetics of mobilization of MM cells compared to other bone marrow cells, and determining whether MM cells mobilized out of the BM will be more sensitive to apoptosis by cytotoxic agents compared to malignant cells residing in the BM. Targeting trafficking will lead to a paradigm shift in therapeutic approaches in MM, where we will alter the capacity of MM cells to reside in their protective bone marrow microenvironment by inducing egression and preventing homing and adhesion, leading to increased sensitivity to apoptosis. PUBLIC HEALTH RELEVANCE: The mechanisms of tumor progression in myeloma are not well understood. We will study the role of the chemokine SDF-1 and its receptors in the regulation of entry of myeloma cells into the bone marrow, their adhesion and their exit into the circulation. Targeting this process by mobilizing myeloma cells out of the marrow will lead to a higher sensitivity to killing of the cells with cytotoxic agents.