Novel MRI Vascular Biomarkers for the Detection of Tumor Invasion

描述（由申请人提供）：近年来，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）的脑肿瘤治疗产生了极大的兴趣。然而，虽然经常在短期内成功，所有目前的抗血管生成治疗最终失败。这种失败归因于癌细胞沿着现有的正常血管生长，称为血管共选择。事实上，在啮齿动物脑肿瘤模型中，抗血管生成疗法最近被证明可以通过血管共选加速肿瘤的侵袭，从而导致抗血管生成疗法的逃逸。因此，迫切需要针对肿瘤血管生成和侵袭的新的联合治疗方法。然而，由于缺乏检测浸润性癌细胞的方法，检测浸润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，浸润性癌细胞吞噬了正常的脉管系统，不表现出通透性升高或水肿，因此MRI无法检测到它们。因此，迫切需要新的方法来检测这些侵袭性肿瘤区域。我们建议研究和验证新型MRI血管生物标志物的使用，这些标志物对侵袭性癌细胞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引起的血管变化敏感。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，该模型与临床观察到的肿瘤生长模式非常相似。我们假设，这些新的MRI血管生物标志物将为浸润性脑肿瘤区域的血管变化和血管选择提供高度敏感的测量，而这些是目前方法无法检测到的。

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.