Delivery issues in lung cancer CNS metastases

肺癌中枢神经系统转移的递送问题

• 批准号: 8803270
• 负责人: EDWARD A. NEUWELT
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803270
• 关键词: A549; Adenocarcinoma; Aftercare; Aging; Angiogenesis Inhibitors; Animal Model; Avastin; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood Volume; Brain; Brain Neoplasms; Cerebrum; Characteristics; Clinical Trials; Combined Modality Therapy; Contrast Media; Cranial Irradiation; Development; Drug Delivery Systems; Evaluation; Gadolinium; Glioblastoma; Goals; Growth; Hematogenous; Heterogeneity; Human; Hypoxia; Image; Imaging Techniques; Immunohistochemistry; Implant; Individual; Inflammation; Large Cell Carcinoma; Lead; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of central nervous system; Malignant neoplasm of lung; Measures; Metastatic Neoplasm to the Central Nervous System; Metastatic malignant neoplasm to brain; Modeling; Molecular Weight; Monoclonal Antibodies; Morbidity - disease rate; Necrosis; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Patients; Permeability; Predisposition; Quantitative Autoradiography; Radiation therapy; Radiolabeled; Rattus; Relative (related person); Squamous cell carcinoma; Subgroup; Testing; Therapeutic Effect; Translating; United States Department of Veterans Affairs; Variant; Vascular Endothelial Growth Factors; Vascular Permeabilities; Weight; Xenograft procedure; base; bevacizumab; chemoradiation; chemotherapy; contrast enhanced; effective therapy; ferumoxytol; gadolinium oxide; improved; iron oxide; lung small cell carcinoma; nanoparticle; novel; outcome forecast; patient population; pre-clinical; radiotracer; research study; response; temozolomide; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）： 脑肿瘤，特别是全身性癌症如肺癌的脑转移，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。目前脑转移瘤的治疗方法如放疗加或不加化疗仅具有短期疗效。脑转移瘤在影像学特征、免疫组化标记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，在血容量和血管通透性方面，个体转移瘤和瘤周脑中血管系统的异质性决定并限制了放化疗治疗的疗效。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系统的异质性，并将肿瘤血容量和血管通透性的变化与药物输送、缺氧、肿瘤生长和脑转移大鼠模型的存活率相关联。使用氧化铁纳米颗粒血池剂ferumoxytol的动态磁共振成像提供了肿瘤血容量的测量，而使用钆基造影剂的动态对比增强MRI提供了血管渗透性和造影剂分布的测量。研究将在代表人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，有或没有替莫唑胺化疗，贝伐单抗（阿瓦斯丁），一种抗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将描述未治疗的异种移植物和血行性脑转移瘤中血管特征和药物递送的异质性。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， 缺氧和坏死。具体目标2将研究WBRT后脑和肿瘤血管系统的早期和晚期变化，以及WBRT联合替莫唑胺治疗后假性进展的证据。在目标3中，我们将评价使用贝伐单抗靶向脑转移瘤血管系统的效果，并评估其对肿瘤缓解与假缓解的影响。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率的影响。对于目标2和3，我们假设血容量和血管通透性的变化与个体肿瘤的生长和生存相关。该转化临床前提案的目标是确定放射治疗或贝伐单抗靶向肿瘤血管对动态MRI的影响，并确定这些方法与化疗联合在肺癌脑转移大鼠模型中的药理学和治疗效果。动态MRI技术在确定胶质母细胞瘤对治疗的反应方面非常有效;本提案的目标是确定这些方法在脑转移瘤中的适用性，并评估其证明抗肿瘤疗效的潜力。我们假设，这些方法将导致动态MRI和新疗法的临床试验的发展，这将转化为提高肺癌脑转移VA患者的生存率。