Inhibition of the SDF-1/CXCR4 axis as preventive therapy for radiation-induced pu

抑制 SDF-1/CXCR4 轴作为辐射诱发 pu 的预防性治疗

• 批准号: 7662028
• 负责人: HYUNSUK SHIM
• 金额: $ 19.38万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-08 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662028
• 关键词: Adverse effects; Alveolar; Area; Attenuated; Bleomycin; Bone Marrow; C57BL/6 Mouse; CXCR4 Receptors; CXCR4 gene; Cancer Patient; Caring; Cells; Chemotaxis; Chest; Clinical Trials; Development; Disease; Dose; Dose-Limiting; Drug Administration Schedule; Fibrosis; Goals; Health; Human; Injury; Late Effects; Lung; Malignant Neoplasms; Patients; Pattern; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Prevention; Preventive; Process; Pulmonary Fibrosis; Radiation; Radiation Injuries; Radiation Protection; Radiation therapy; Recruitment Activity; Risk; Role; Serum; Shortness of Breath; Stem cells; Stromal Cell-Derived Factor 1; Structure; Structure of parenchyma of lung; Time; Toxic effect; Translating; Treatment Protocols; Work; chemokine; chemotherapy; drug candidate; fibrogenesis; in vivo; inhibitor/antagonist; injured; interstitial; irradiation; lung development; lung injury; mouse model; novel; patient population; pre-clinical; prevent; public health relevance; receptor binding; response; small molecule; tumor

DESCRIPTION (provided by applicant): Many patients with intrathoracic malignancies will receive radiation therapy for the treatment for their disease. This often necessitates exposure of significant portions of their lung to high doses of radiation. One particularly devastating late injury caused by radiation is pulmonary fibrosis. This problem develops as progressive shortness of breath with increasing interstitial lung fibrosis and loss of alveolar structures. The risk of pulmonary fibrosis may limit the volume of irradiation and compromise a potentially curative therapy. Therefore, development of a therapy to prevent this toxicity can be of great benefit for this patient population. Stromal cell-derived factor 1 (SDF-1/CXCL12) is a chemokine that through interactions with its receptor CXCR4 may play an important role in the fibrotic response through recruitment of bone marrow-derived progenitor cells to the injured lung. The chemotaxis of these cells to an area of lung injury is believed to be a critical step in the ultimate development pulmonary fibrosis. In mouse models of bleomycin-induced pulmonary fibrosis, inhibitors of CXCR4 can significantly decrease the development of lung fibrosis. We have recently developed an inhibitor of CXCR4 (WZ40) that binds this receptor in the nM range and may induce less toxicity than other currently available CXCR4 antagonists. In our preliminary work, we also find that WZ40 can similarly block bleomycin-induced lung fibrosis. Although the latency period for development of lung fibrosis after radiation exposure is longer than that observed with bleomycin, we hypothesize that radiation-induced fibrosis likely occurs via a similar mechanism to that induced by the lung-toxic chemotherapy and involves recruitment of CXCR4+ bone marrow-derived progenitor cells. Thus, we believe that CXCR4 inhibition will also inhibit pulmonary fibrosis after lung irradiation. In our initial Aim, we plan to determine 1) whether SDF-1 levels are increased after lung irradiation, 2) whether this leads to recruitment of CXCR4+ stem cells which helps drive fibrogenesis, and 3) whether our CXCR4 antagonist WZ40 can block the recruitment of these CXCR4+ stem cells. In our second Aim, we intend to determine whether WZ40 can inhibit the development of radiation-induced pulmonary fibrosis in an established C57BL/6 mouse model. Here, we hope to also establish the optimal dosing regimen for this drug. The primary goal of this study is to determine the potential utility of this new drug in the prevention of radiation-induced pulmonary fibrosis and to hopefully carry it forward in clinical trial for this problem. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to evaluate a new drug for its ability to suppress the development of radiation- induced pulmonary fibrosis. This late effect of radiation therapy may potentially limit the dose and extent of radiation therapy used for thoracic malignancies. If successful, this drug may be carried forward to clinical trial to attempt to prevent this potentially debilitating side effect of radiation treatments.

描述（由申请人提供）：许多胸腔内恶性肿瘤患者将接受放射治疗来治疗他们的疾病。这通常需要将肺部的很大一部分暴露在高剂量的辐射下。辐射引起的一种特别具有破坏性的晚期损伤是肺纤维化。这个问题随着肺间质纤维化的增加和肺泡结构的丧失而发展为进行性呼吸短促。肺纤维化的风险可能会限制照射量并损害潜在的治愈性治疗。因此，开发一种预防这种毒性的疗法对该患者群体有很大好处。基质细胞衍生因子 1 (SDF-1/CXCL12) 是一种趋化因子，通过与其受体 CXCR4 相互作用，可能通过将骨髓源性祖细胞募集到受损肺部，在纤维化反应中发挥重要作用。这些细胞对肺损伤区域的趋化被认为是最终发展为肺纤维化的关键步骤。在博莱霉素诱导的肺纤维化小鼠模型中，CXCR4 抑制剂可以显着减少肺纤维化的发展。我们最近开发了一种 CXCR4 抑制剂 (WZ40)，它在 nM 范围内与该受体结合，并且可能比其他目前可用的 CXCR4 拮抗剂诱导更少的毒性。在我们的前期工作中，我们还发现 WZ40 可以类似地阻断博莱霉素诱导的肺纤维化。尽管辐射暴露后肺纤维化发展的潜伏期比博莱霉素观察到的潜伏期长，但我们推测辐射诱导的纤维化可能通过与肺毒性化疗诱导的相似机制发生，并涉及CXCR4+骨髓源性祖细胞的募集。因此，我们相信CXCR4抑制也会抑制肺部照射后的肺纤维化。在我们最初的目标中，我们计划确定 1) 肺部照射后 SDF-1 水平是否增加，2) 这是否会导致 CXCR4+ 干细胞的募集，从而有助于驱动纤维形成，以及 3) 我们的 CXCR4 拮抗剂 WZ40 是否可以阻止这些 CXCR4+ 干细胞的募集。在我们的第二个目标中，我们打算确定 WZ40 是否可以在已建立的 C57BL/6 小鼠模型中抑制辐射诱导的肺纤维化的发展。在这里，我们也希望建立这种药物的最佳给药方案。这项研究的主要目标是确定这种新药在预防辐射引起的肺纤维化方面的潜在效用，并希望在该问题的临床试验中继续推进。 公众健康相关性：本提案的目的是评估一种新药抑制辐射诱发肺纤维化发展的能力。放射治疗的这种迟发效应可能会限制用于胸部恶性肿瘤的放射治疗的剂量和程度。如果成功，这种药物可能会进入临床试验，以试图防止放射治疗的这种潜在的使人衰弱的副作用。