DCE-MRI for Assessment of Vascular Normalization by Nelfinavir in Lung Cancer

描述（由申请人提供）：局部晚期非小细胞肺癌（NSCLC）的确定性放疗局部控制极差，活检证实的1年局部失败率高达80%。这可能是由于肿瘤对放疗的显著抵抗。血管内皮生长因子（VEGF）信号通路的抑制剂已被证明在体外和体内都起辐射增敏剂的作用。这种辐射致敏机制的一种假设是VEGF抑制修剪不成熟的脉管系统，导致肿瘤血流正常化，这反过来又允许增加向肿瘤的氧气输送。肿瘤氧合的增加导致响应于电离辐射的增强的活性氧物质形成，从而允许更大的DNA损伤。这一假设得到了以下观察结果的支持：通过动态对比增强成像量化的放疗后肿瘤血流动力学改善的患者对治疗的反应改善。我们的研究小组和其他人已经表明，奈非那韦调节VEGF信号传导，并改善动物模型中的肿瘤灌注和氧合。我们也有使用DCE-MRI的初步临床数据，表明奈非那韦给药后肿瘤血管通透性降低，提示血流正常化。我们最近完成了一项奈非那韦与同步放化疗治疗局部晚期非小细胞肺癌患者的I期试验。我们观察到这些患者在13个月的随访中，总体缓解率为100%，完全代谢缓解率为58%，局部控制率为92%。我们解释这些临床结果的假设是，奈非那韦给药通过血管正常化导致NSCLC的放射增敏。因此，我们建议利用DCE-MRI肿瘤成像来评估局部晚期NSCLC患者对奈非那韦治疗的血管正常化。本项目的总体目标是确定奈非那韦给药是否导致局部晚期NSCLC患者血管通透性降低，并确定这种降低是否与临床结局相关。最后，我们将探讨接受奈非那韦治疗的患者对放化疗的渗透性反应的大小与肿瘤对治疗的反应之间的关系。在此过程中，我们将探讨一个基本问题：奈非那韦能否有利地改变局部晚期NSCLC的肿瘤微环境，以克服外源性肿瘤对确定性放化疗的耐药性？ 公共卫生相关性：肺癌对公共卫生造成破坏性影响，每年新发病例20万例，死亡人数约17.5万人。超过50%的肺癌患者接受明确的放射治疗;然而，这些患者中的大多数没有治愈，几乎60-80%的患者经历了疾病的复发。本项目的目的是确定动态对比增强磁共振成像是否可以记录Nelfinavir（一种已知的放射增敏剂）对肿瘤血流动力学的正常化，以及这种改善是否会改善对放射治疗的反应。

DESCRIPTION (provided by applicant): Local control with definitive radiotherapy in locally advanced non-small cell lung cancer (NSCLC) is extremely poor with biopsy proven local failure rates at one year as high as 80%. This is likely due to significant tumor resistance to radiotherapy. Inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway have been shown to function as radiation sensitizers both in vitro and in vivo. One hypothesis for the mechanism of this radiation sensitization is that VEGF inhibition prunes immature vasculature, resulting in normalization of tumor blood flow, which in turn allows for increased oxygen delivery to the tumor. The increase in tumor oxygenation results in enhanced reactive oxygen species formation in response to ionizing radiation allowing for greater DNA damage. This hypothesis is supported by the observation that patients with improved tumor hemodynamics after radiotherapy as quantified by dynamic contrast enhanced imaging have an improved response to treatment. Our group and others have shown that Nelfinavir modulates VEGF signaling and improves tumor perfusion and oxygenation in animal models. We also have preliminary clinical data using DCE-MRI that suggests a decrease in tumor vascular permeability with administration of Nelfinavir, suggestive of blood flow normalization. We have recently completed a phase I trial of Nelfinavir with concurrent chemoradiotherapy in patients with locally advanced NSCLC. We observed a promising 100% overall response rate, 58% complete metabolic response rate, and local control rate of 92% with 13 months follow-up in these patients. Our hypothesis to explain these clinical results is that Nelfinavir administration results in radiosensitization of NSCLC through vascular normalization. We therefore propose to utilize DCE-MRI tumor imaging to assess vascular normalization in patients with locally advanced NSCLC in response to treatment with Nelfinavir. The overall objective of this project is to determine whether Nelfinavir administration results in decreased vascular permeability in patients with locally advanced NSCLC and to determine if this decrease correlates with clinical outcome. Finally, we will explore the relationship between the magnitude of the permeability response to chemoradiotherapy in patients receiving Nelfinavir and tumor response to treatment. In doing this we will explore the fundamental question: Can Nelfinavir favorably alter the tumor microenvironment in locally advanced NSCLC to overcome extrinsic tumor resistance to definitive chemoradiotherapy? PUBLIC HEALTH RELEVANCE: Lung cancer exacts a devastating impact on public health with 200,000 new cases each year with approximately 175,000 deaths. Greater than 50% of patients with lung cancer receive definitive radiotherapy; however, the majority of these patients are not cured with almost 60-80% of patients experiencing a relapse of their disease. The purpose of this project is to determine whether dynamic contrast enhanced magnetic resonance imaging can document the normalization of tumor hemodynamics by Nelfinavir, a known radiation sensitizer, and whether this improvement results in an improved response to radiation treatment.