Delivery issues in lung cancer CNS metastases

描述(由申请人提供)： 脑瘤，特别是肺癌等系统性癌症的脑转移，在退伍军人管理局的患者群体中是一个日益严重的问题，并与高发病率和不良预后有关。目前脑转移瘤的治疗方法，如放射治疗加或不加化疗，都只有短期疗效。脑转移瘤在影像特征、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。我们推测，在单个转移瘤和瘤周脑中，血管系统的异质性，无论是在血容量还是血管通透性方面，都决定和限制了化疗和放疗的疗效。我们建议使用新的动态磁共振成像(MRI)技术来评估脑肿瘤血管的异质性，并在脑转移模型中将肿瘤血容量和血管通透性的变化与药物输送、缺氧、肿瘤生长和生存联系起来。使用氧化铁纳米颗粒血池试剂阿魏酸甲酯的动态磁化率加权MRI提供了肿瘤血量的测量，而使用基于Gd的造影剂的动态对比增强MRI提供了血管渗透性和对比度分布的测量。将在血液和脑内异种移植动物模型中进行研究，这些动物模型代表了人类肺癌的四个主要组织病理亚组：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。治疗范例将是加或不加替莫唑胺化疗的全脑放射治疗，以及贝伐单抗(阿瓦斯丁)，这是一种对人脑肿瘤有效的抗血管内皮生长因子的单抗。具体目标1将表征未经治疗的异种移植和血源性脑转移瘤的血管特征和药物输送的异质性。我们假设肿瘤的血管通透性与药物输送有关，而血容量与炎症有关， 单个转移瘤中的缺氧和坏死。具体目标2将研究WBRT后脑血管和肿瘤血管的早期和晚期变化，以及WBRT加替莫唑胺治疗后假性进展的证据。在目标3中，我们将评估贝伐单抗在脑转移瘤中靶向血管系统的效果，并评估其对肿瘤反应和假反应的影响。我们将评估贝伐单抗、WBRT和替莫唑胺联合治疗对血管特性和存活率的影响。对于目标2和目标3，我们假设血容量和血管通透性的变化将与单个肿瘤的生长和生存相关。这项翻译的临床前建议的目的是确定放射治疗或贝伐单抗靶向肿瘤血管对动态磁共振成像的影响，并确定这些方法与化疗联合应用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的治疗反应方面是非常有效的；本提案的目的是确定这些方法在脑转移瘤中的适用性，并评估它们展示抗肿瘤疗效的潜力。我们假设这些方法将导致动态核磁共振的临床试验和新的治疗方法的发展，这将转化为改善VA肺癌脑转移患者的生存。

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.