Delivery issues in lung cancer CNS metastases

描述（由申请人提供）： 脑肿瘤，特别是肺癌等全身性癌症的脑转移，是退伍军人管理局患者群体中日益严重的问题，并且与高发病率和不良预后相关。目前脑转移的治疗方法，例如放疗联合或不联合化疗，仅具有短期疗效。脑转移瘤在影像学特征、免疫组织化学标记物和化疗敏感性方面表现出广泛的异质性，即使在同一患者的不同转移瘤之间也是如此。我们假设个体转移瘤和瘤周脑中脉管系统在血容量和血管通透性方面的异质性决定并限制了放化疗的疗效。我们建议使用新的动态磁共振成像（MRI）技术评估脑肿瘤脉管系统的异质性，并将肿瘤血容量和血管通透性的变化与脑转移大鼠模型中的药物输送、缺氧、肿瘤生长和存活相关联。使用氧化铁纳米粒子血池剂费鲁莫托尔的动态磁敏感加权 MRI 可测量肿瘤血容量，而使用钆造影剂的动态对比增强 MRI 可测量血管通透性和对比度分布。研究将在代表人类肺癌四个主要组织病理学亚组的血源性和脑内异种移植动物模型中进行：LX-1小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC）变体H460大细胞癌、H520鳞状细胞癌和A549腺癌。治疗范例将是全脑放射治疗，联合或不联合替莫唑胺化疗和贝伐单抗（阿瓦斯汀），贝伐单抗是一种针对血管内皮生长因子的单克隆抗体，对人类脑肿瘤有效。具体目标 1 将描述未经治疗的异种移植瘤和血行脑转移瘤中血管特征和药物输送的异质性。我们假设肿瘤血管通透性与药物输送相关，而血容量与炎症相关， 缺氧和个别转移坏死。具体目标 2 将调查 WBRT 后大脑和肿瘤脉管系统的早期和晚期变化，以及 WBRT 加替莫唑胺治疗后假性进展的证据。在目标 3 中，我们将评估使用贝伐单抗靶向脑转移瘤中脉管系统的效果，并评估其对肿瘤反应与假反应的影响。我们将评估贝伐单抗、WBRT 和替莫唑胺联合治疗对血管特征和生存的影响。对于目标 2 和 3，我们假设血容量和血管通透性的变化将与个体肿瘤的生长和生存相关。这项转化性临床前提案的目标是确定用放射疗法或贝伐珠单抗靶向肿瘤脉管系统对动态 MRI 的影响，并确定这些方法与化疗相结合在肺癌脑转移大鼠模型中的药理和治疗效果。动态 MRI 技术在确定胶质母细胞瘤治疗反应方面非常有效；该提案的目标是确定这些方法在脑转移中的适用性，并评估它们展示抗肿瘤功效的潜力。我们假设这些方法将促进动态 MRI 临床试验和新疗法的发展，从而提高患有肺癌脑转移的 VA 患者的生存率。

DESCRIPTION (provided by applicant): Brain tumors, particularly brain metastases of systemic cancers such as lung cancer, are a growing problem in the Veterans Administration patient population, and are associated with high morbidity and poor prognosis. Current treatments for brain metastasis such as radiotherapy with or without chemotherapy have only short- term efficacy. Brain metastases show wide heterogeneity in imaging characteristics, immunohistochemical markers, and chemotherapy sensitivity, even among different metastases in the same patient. We postulate that the heterogeneity of the vasculature in individual metastases and peritumoral brain, in terms of both blood volume and vessel permeability, determines and limits the efficacy of chemo-radiotherapy treatments. We propose to evaluate the heterogeneity of brain tumor vasculature using new dynamic magnetic resonance imaging (MRI) techniques, and correlate changes in tumor blood volume and vascular permeability with drug delivery, hypoxia, tumor growth and survival in rat models of brain metastasis. Dynamic susceptibility-weighted MRI with the iron oxide nanoparticle blood pool agent ferumoxytol provides a measure of tumor blood volume while dynamic contrast-enhanced MRI with gadolinium-based contrast agents provides measures of vascular permeability and contrast distribution. Studies will be performed in hematogenous and intracerebral xenograft animal models representative of the four major histopathological subgroups of human lung cancer: LX-1 small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) variants H460 large cell carcinoma, H520 squamous cell carcinoma, and A549 adenocarcinoma. Treatment paradigms will be whole brain radiation therapy with or without temozolomide chemotherapy, and bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor that is effective in human brain tumors. Specific Aim 1 will characterize the heterogeneity of vascular characteristics and drug delivery in untreated xenograft and hematogenous brain metastases. We hypothesize that the tumor vascular permeability will correlate with drug delivery while blood volume will correlate with inflammation, hypoxia, and necrosis in individual metastases. Specific Aim 2 will investigate early and late changes in brain and tumor vasculature following WBRT, and evidence for pseudoprogression after treatment with WBRT plus temozolomide. In Aim 3 we will evaluate the effect of targeting the vasculature in brain metastases using bevacizumab and assess its impact on tumor response versus pseudoresponse. We will assess the effect of combination therapy with bevacizumab, WBRT, and temozolomide on vascular characteristics and survival. For both Aims 2 and 3, we hypothesize that changes in blood volume and vascular permeability will correlate with the growth of individual tumors and survival. The goals of this translational preclinical proposal are to define the effects of targeting tumor vasculature with radiotherapy or bevacizumab on dynamic MRI and to determine the pharmacological and therapeutic effects of these approaches in combination with chemotherapy in rat models of lung cancer brain metastasis. The dynamic MRI techniques are highly effective in determining response to therapy in glioblastoma; the goal of this proposal is to determine the applicability of these approaches in brain metastases and evaluate their potential to demonstrate anti-tumor efficacy. We hypothesize that these approaches will lead to the development of a clinical trial of dynamic MRI and novel therapy that will translate into improved survival of VA patients with lung cancer brain metastases.