Novel MRI Vascular Biomarkers for the Detection of Tumor Invasion

用于检测肿瘤侵袭的新型 MRI 血管生物标志物

• 批准号: 8114363
• 负责人: CHRISTIAN T FARRAR
• 金额: $ 23.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114363
• 关键词: Biological Markers; Bioluminescence; Blood Vessels; Blood Volume; Brain; Brain Neoplasms; Caliber; Cancer Cell Growth; Cancer cell line; Cells; Characteristics; Clinical; Clinical Data; Combined Modality Therapy; Contralateral; Data; Detection; Development; Edema; Epidermal Growth Factor Receptor; Excision; Exhibits; Failure; Generations; Glioblastoma; Glioma; Growth; Growth Factor; Histology; Human; In Vitro; Magnetic Resonance Imaging; Measures; Membrane; Methods; Modeling; Monitor; Mus; Neoplasms in Vascular Tissue; PECAM1 gene; Pattern; Permeability; Proliferating; Relative (related person); Rodent; Signal Transduction; Stroke; Tissues; Tumor Angiogenesis; Tumor Cell Invasion; Up-Regulation; Vascular Endothelial Growth Factors; Vascular Permeabilities; Water; angiogenesis; antitumor agent; aquaporin 4; base; brain tissue; cancer cell; cellular engineering; chemotherapy; human FRAP1 protein; imaging modality; improved; in vivo; indexing; interest; kinase inhibitor; neoplastic cell; novel; pre-clinical; response; stem; subcutaneous; tool; tumor; tumor growth; water channel

DESCRIPTION (provided by applicant): Recently there has been great interest in brain tumor therapies that suppress growth factors generated by cancer cells for the generation of new blood vessels (angiogenesis). However, while frequently successful in the short term, all current anti- angiogenic therapies eventually fail. This failure has been attributed to invasive cancer cell growth along existing normal vasculature, termed vessel co-option. Indeed, anti- angiogenic therapies in rodent brain tumor models have recently been shown to accelerate tumor invasion by vessel co-option, leading to escape from anti-angiogenic therapy. New combination therapies that target both tumor angiogenesis and invasion are therefore urgently needed. However, detecting invasive tumor regions and assessing their response to potential therapies is complicated by the lack of methods for detecting such invasive cancer cells. Conventional Magnetic Resonance Imaging (MRI) methods detect the elevated vascular permeability and edema that are characteristic of angiogenesis driven tumor growth. Invasive cancer cells that co-opt normal vasculature, however, do not display elevated permeability or edema, thereby rendering them invisible to MRI. New methods are therefore urgently needed for detecting such invasive tumor regions. We propose to investigate and validate the use of novel MRI vascular biomarkers that are sensitive to vascular changes induced by invasive cancer cells in the absence of angiogenesis and its associated elevated edema and vascular permeability. We will also investigate the sensitivity of these new MRI biomarkers to changes induced by anti- tumor therapy. These studies will be performed in invasive mouse brain tumor models that closely mimic tumor growth patterns observed clinically. We hypothesize that these novel MRI vascular biomarkers will provide highly sensitive measures of vascular changes and vessel co-option in invasive brain tumor regions that are not detectable by current methods. PUBLIC HEALTH RELEVANCE: No clinical methods are currently available for the detection of invasive tumor regions that grow by vessel co-option. The development of MRI biomarkers of tumor invasion is therefore critical for (1) the detection of invasive tumor borders, thereby improving tumor resection, (2) the detection of escape from anti-angiogenic therapy, and (3) monitoring the response of invasive cancer cells to new tumor therapies that target both tumor angiogenesis and invasion.

描述（由申请人提供）：最近，人们对抑制癌细胞产生的生长因子以产生新血管（血管生成）的脑肿瘤疗法产生了极大的兴趣。然而，虽然在短期内经常取得成功，但所有当前的抗血管生成疗法最终都会失败。这种失败归因于侵袭性癌细胞沿现有正常脉管系统生长，称为血管共选。事实上，最近已证明啮齿动物脑肿瘤模型中的抗血管生成疗法可通过血管选择加速肿瘤侵袭，从而导致逃避抗血管生成疗法。因此，迫切需要针对肿瘤血管生成和侵袭的新联合疗法。然而，由于缺乏检测这种侵袭性癌细胞的方法，检测侵袭性肿瘤区域并评估其对潜在疗法的反应变得复杂。传统的磁共振成像 (MRI) 方法可检测血管通透性升高和水肿，这是血管生成驱动肿瘤生长的特征。然而，吸收正常脉管系统的侵袭性癌细胞不会表现出渗透性升高或水肿，从而使它们在 MRI 中不可见。因此，迫切需要新的方法来检测这种侵袭性肿瘤区域。 我们建议研究和验证新型 MRI 血管生物标志物的使用，这些生物标志物在没有血管生成及其相关的水肿和血管通透性升高的情况下，对侵袭性癌细胞诱导的血管变化敏感。我们还将研究这些新的 MRI 生物标志物对抗肿瘤治疗引起的变化的敏感性。这些研究将在侵袭性小鼠脑肿瘤模型中进行，该模型密切模仿临床观察到的肿瘤生长模式。我们假设这些新型 MRI 血管生物标志物将为目前方法无法检测到的侵袭性脑肿瘤区域的血管变化和血管选择提供高度灵敏的测量。 公共健康相关性：目前没有临床方法可用于检测通过血管共选生长的侵袭性肿瘤区域。因此，肿瘤侵袭的 MRI 生物标志物的开发对于以下方面至关重要：(1) 检测侵袭性肿瘤边界，从而改善肿瘤切除；(2) 检测逃避抗血管生成治疗的情况；(3) 监测侵袭性癌细胞对针对肿瘤血管生成和侵袭的新肿瘤疗法的反应。