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

描述(申请人提供)：许多胸腔内恶性肿瘤患者将接受放射治疗。这往往需要他们的肺的很大一部分暴露在高剂量的辐射下。辐射造成的一种特别严重的晚期损伤是肺纤维化。这个问题发展为进行性呼吸短促，伴随着间质性肺纤维化的增加和肺泡结构的丧失。肺纤维化的风险可能会限制照射的量，并危及潜在的根治疗法。因此，开发一种预防这种毒性的治疗方法对这一患者群体有很大的好处。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的相互作用，可能通过向受损肺募集骨髓来源的祖细胞而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。在博莱霉素诱导的小鼠肺纤维化模型中，CXCR4抑制剂可显著抑制肺纤维化的发展。我们最近开发了一种CXCR4的抑制剂(WZ40)，它可以在NM范围内结合这种受体，并且可能比目前可用的其他CXCR4拮抗剂诱导的毒性更小。在我们的初步工作中，我们还发现WZ40类似地可以阻断博莱霉素诱导的肺纤维化。尽管辐射后肺纤维化的潜伏期比博莱霉素组要长，但我们推测放射性肺纤维化可能通过与肺毒性化疗相似的机制发生，并涉及CXCR4+骨髓来源的祖细胞的募集。因此，我们认为抑制CXCR4也能抑制肺照射后的肺纤维化。在我们最初的目标中，我们计划确定1)肺照射后SDF-1水平是否增加，2)这是否导致有助于推动纤维化形成的CXCR4+干细胞的招募，以及3)我们的CXCR4拮抗剂WZ40是否可以阻止这些CXCR4+干细胞的招募。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小鼠模型中抑制放射性肺纤维化的发展。在这里，我们也希望建立该药物的最佳给药方案。这项研究的主要目的是确定这种新药在预防放射性肺纤维化方面的潜在效用，并有望在这一问题的临床试验中继续进行。 公共卫生相关性：这项提案的目标是评估一种新药抑制放射性肺纤维化发展的能力。这种放射治疗的后期效应可能会限制用于胸部恶性肿瘤的放射治疗的剂量和范围。如果成功，这种药物可能会被带入临床试验，试图防止这种可能使人虚弱的放射治疗副作用。

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.