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

描述（由申请方提供）：许多胸内恶性肿瘤患者将接受放射治疗以治疗其疾病。这通常需要将其肺的大部分暴露于高剂量的辐射。由辐射引起的一种特别具有破坏性的晚期损伤是肺纤维化。该问题发展为进行性呼吸短促，伴有肺间质纤维化增加和肺泡结构丧失。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治疗方法可能对该患者人群有很大的益处。基质细胞衍生因子1（SDF-1/CXCL 12）是一种趋化因子，通过与其受体CXCR 4的相互作用，可通过将骨髓来源的祖细胞募集到损伤的肺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性被认为是最终发展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，CXCR 4抑制剂可显著降低肺纤维化的发展。我们最近开发了一种CXCR 4抑制剂（WZ 40），其在nM范围内结合该受体，并且可能比其他目前可用的CXCR 4拮抗剂诱导更少的毒性。在我们的初步工作中，我们还发现WZ 40可以类似地阻断博莱霉素诱导的肺纤维化。尽管放射暴露后肺纤维化发展的潜伏期长于博莱霉素，但我们假设放射诱导的纤维化可能通过与肺毒性化疗诱导的机制相似的机制发生，并涉及CXCR 4+骨髓源性祖细胞的募集。因此，我们相信CXCR 4抑制也将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CXCR 4+干细胞的募集，这有助于驱动纤维化，以及3）我们的CXCR 4拮抗剂WZ 40是否可以阻断这些CXCR 4+干细胞的募集。在我们的第二个目标中，我们打算确定WZ 40是否可以在已建立的C57 BL/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。本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，并希望将其用于该问题的临床试验。 公共卫生相关性：该提案的目的是评估一种新药抑制放射性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胸部恶性肿瘤放射治疗的剂量和范围。如果成功的话，这种药物可能会进行临床试验，试图防止这种潜在的放射治疗的副作用。

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.