Targeting the Bone Marrow Microenvironment In Acute Lymphocytic Leukemia

成人急性淋巴细胞性白血病(ALL)的预后仍然很差。而90%的成年患者 将通过化疗达到初步缓解，大多数人将复发，只有30%-40%的人将达到 长期无病生存。有证据表明，类似于正常的造血干/祖细胞 细胞，白血病细胞从骨髓微环境接收关键的生长和生存信号。 此外，白血病细胞与骨髓基质细胞的直接物理相互作用可能会限制它们的生长。 对化疗敏感。因此，靶向白血病-间质相互作用是一种新兴的和有前途的 使白血病细胞对细胞毒化疗敏感的策略。 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生态位。的确， 在开始化疗之前使用G-CSF可以增强小鼠体内所有细胞的清除。我们发起了 在复发性急性淋巴细胞白血病患者抢救化疗前预先给予G-CSF治疗的试点临床试验。 初步数据显示，G-CSF诱导所有细胞动员进入血液，同时诱导细胞凋亡 所有驻留在骨髓中的细胞。有强有力的证据表明，CXCL12提供了一个关键的生存 正常和恶性淋巴细胞的信号。初步数据显示，用一种新型的POL5551治疗 和强大的CXCR4拮抗剂，动员所有细胞进入小鼠的血液中，使它们对 化疗。由于G-CSF只能部分抑制CXCL12在骨髓中的表达，我们 假设G-CSF和CXCR4拮抗剂将协同作用破坏白血病间质 细胞信号，使所有细胞对化疗更敏感。提出了以下具体目标。 目的1.优化策略以破坏白血病在骨髓中的生态位并使人类急性淋巴细胞白血病敏化 细胞进行化疗。 目的2.探讨粒细胞集落刺激因子(G-CSF)和POL6326联合化疗在成人慢性粒细胞白血病化疗中应用的可行性。 复发或难治性ALL。 相关性(请参阅说明)： 这项拟议的研究与公共卫生相关，因为它试图将基本观察转化为 G-CSF和CXCR信号转导对早期临床试验的影响 改善急性淋巴细胞白血病患者的临床转归。

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.