Targeting the Bone Marrow Microenvironment In Acute Lymphocytic Leukemia

针对急性淋巴细胞白血病的骨髓微环境

• 批准号: 8595788
• 负责人: GEOFFREY L UY
• 金额: $ 33.99万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-03 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595788
• 关键词: Acute Lymphocytic Leukemia; Adult; Apoptosis; Blood; Bone Marrow; CSF3 gene; CXCL12 gene; CXCR; CXCR4 gene; Cells; Clinical; Clinical Trials; Cytotoxic Chemotherapy; Data; Disease remission; Disease-Free Survival; Goals; Growth; Hematopoietic; Human; Instruction; Leukemic Cell; Methods; Modeling; Mus; Outcome; Patients; Phase; Public Health; Refractory; Relapse; Research; Signal Pathway; Signal Transduction; Stem cells; Stromal Cells; Testing; Translating; Xenograft procedure; bone; chemotherapy; granulocyte; improved; leukemia; malignant lymphocyte; novel; preclinical study; programs; stem

The outcome of adults with acute lymphoblastic leukemia (ALL) remains poor. While 90% of adult patients will achieve an initial remission with chemotherapy, the majority will relapse and only 30-40% will achieve long-term disease free survival. Evidence suggests that similar to normal hematopoietic stem/progenitor cells, leukemic cells receive key growth and survival signals from the bone marrow microenvironment. Moreover, direct physical interaction of leukemic cells with stromal cells in the bone marrow may limit their sensitivity to chemotherapy. Thus, targeting leukemia-stromal interactions is an emerging and promising strategy to sensitize leukemic cells to cytotoxic chemotherapy. Preclinical studies performed by our group suggest that treatment with granulocyte-stimulating factor (G- CSF) provides a potent and well-tolerated method to disrupt the leukemia niche in the bone marrow. Indeed, treatment with G-CSF prior to initiating chemotherapy augments clearance of ALL cells in mice. We initiated a pilot clinical trial of upfront G-CSF treatment prior to salvage chemotherapy in patients with relapsed ALL. Preliminary data show that G-CSF induces mobilization of ALL cells into the blood, while inducing apoptosis of ALL cells resident in the bone marrow. There is strong evidence that CXCL12 provides a key survival signal for normal and malignant lymphocytes. Preliminary data show that treatment with POL5551, a novel and potent CXCR4 antagonist, mobilizes ALL cells into the blood in mice and renders them more sensitive to chemotherapy. Since G-CSF results in only partial suppression of CXCL12 in the bone marrow, we hypothesize that treatment with G-CSF and a CXCR4 antagonist will cooperate to disrupt leukemia-stromal cell signals, rendering ALL cells more sensitive to chemotherapy. The following specific aims are proposed. Aim 1. To optimize strategies to disrupt the leukemic niche in the bone marrow and sensitize human ALL cells to chemotherapy. Aim 2. To test the feasibility of priming with G-CSF and POL6326 with chemotherapy in adults with relapsed or refractory ALL. RELEVANCE (See instructions): This proposed research is relevant to public health because it seeks to translate fundamental observations on the effects of G-CSF and CXCR signalling in to an early phase clinical trial with an overall goal of improving the clinical outcomes of patients with acute lymphoblastic leukemia.

成人急性淋巴细胞白血病（ALL）的预后仍然很差。90%的成年患者 如果患者在化疗后达到初始缓解，大多数患者会复发，只有30-40%的患者会达到缓解， 长期无病生存。有证据表明，与正常造血干/祖细胞类似， 细胞，白血病细胞从骨髓微环境接收关键的生长和存活信号。 此外，白血病细胞与骨髓中的基质细胞的直接物理相互作用可能限制它们的增殖。 对化疗的敏感性因此，靶向白血病间质相互作用是一个新兴的和有前途的 使白血病细胞对细胞毒性化疗敏感策略。 我们小组进行的临床前研究表明，粒细胞刺激因子（G- CSF）提供了一种有效且耐受性良好的方法来破坏骨髓中的白血病小生境。的确， 在开始化疗之前用G-CSF治疗增加了小鼠中ALL细胞的清除。我们发起 一项在复发性ALL患者中进行挽救性化疗前预先G-CSF治疗的初步临床试验。 初步数据显示，G-CSF诱导ALL细胞动员进入血液，同时诱导细胞凋亡 所有的细胞都存在于骨髓中。有强有力的证据表明，CXCL 12提供了关键的生存 正常和恶性淋巴细胞信号。初步数据显示，用POL 5551治疗，一种新的 和有效的CXCR 4拮抗剂，在小鼠中动员ALL细胞进入血液，并使它们对 化疗由于G-CSF仅部分抑制骨髓中的CXCL 12，因此，我们 假设用G-CSF和CXCR 4拮抗剂治疗将协同破坏白血病间质 细胞信号，使ALL细胞对化疗更敏感。提出了以下具体目标。 目标1.优化策略，破坏骨髓中的白血病生态位并致敏人类ALL 细胞进行化疗。 目标2.为了测试用G-CSF和POL 6326预充与化疗在成人中的可行性， 复发性或难治性ALL。 相关性（参见说明）： 这项拟议中的研究与公共卫生有关，因为它试图将基本观察转化为 G-CSF和CXCR信号传导的影响，进行早期临床试验，总体目标是 改善急性淋巴细胞白血病患者的临床结局。