Using 18F-EF5 PET to measure hypoxia modulation by Nelfinavir in larynx cancer

使用 18F-EF5 PET 测量奈非那韦对喉癌的缺氧调节

• 批准号: 8695592
• 负责人: Alexander Lin
• 金额: $ 45.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-10 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695592
• 关键词: A-factor (Streptomyces); Affect; Antioxidants; Biological Assay; Biological Markers; Cells; Cessation of life; Cisplatin; Clinic; Clinical; Clinical Data; Clinical Trials; Complex; Consumption; Data; Disease; Disease-Free Survival; Disorder by Site; Dose; EF5; Effectiveness; Future; Genetic Epistasis; Glucose; Goals; HIV; HIV Protease Inhibitors; HPV-High Risk; Head and Neck Squamous Cell Carcinoma; High Prevalence; Human Papillomavirus; Hypoxia; Image; In Vitro; Laboratory Study; Laryngectomy; Lead; Light; Malignant Neoplasms; Malignant neoplasm of larynx; Malignant neoplasm of lung; Measures; Mediating; Membrane Potentials; Mitochondria; Modification; Morbidity - disease rate; Morphology; Nelfinavir; Organ Preservation; Outcome; Oxygen; PET/CT scan; Pathway interactions; Patients; Pentose Phosphate Cycle Pathway; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphorylation; Population; Positron-Emission Tomography; Pre-Clinical Model; Progression-Free Survivals; Protease Inhibitor; Proteins; Radiation; Radiation Tolerance; Radiation therapy; Radiosensitization; Recording of previous events; Recurrence; Relapse; Role; SLC2A1 gene; Scanning; Serum Markers; Signal Transduction; Solid; Solid Neoplasm; Staging; Testing; Toxic effect; Translating; Tumor Oxygenation; cancer type; cell killing; chemoradiation; chemotherapy; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose uptake; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; non-invasive imaging; novel; novel strategies; outcome forecast; overexpression; patient population; pre-clinical; public health relevance; randomized trial; research study; response; treatment planning; tumor

DESCRIPTION (provided by applicant): Radiation therapy (RT) is commonly used to treat solid tumors~ however, even with sophisticated treatment planning and dose delivery, the local control for many cancers remains poor. One clear example is high-risk (human papilloma virus (HPV)-negative), locally-advanced head and neck squamous cell carcinoma (LA-HNSCC), where local recurrences are common and cause significant morbidity and death. One factor strongly associated with local recurrence following RT in LA-HNSCC is tumor hypoxia. Consistent with this, hypoxia modification has been shown to improve local control and overall survival in patients with HNSCC, particularly in those with HPV-negative disease. We have found in pre-clinical models that nelfinavir (NFV), a HIV protease inhibitor with a long history of use in the clinic, decreases tumor hypoxia, which may increase extrinsic radiosensitivity. Additionally, NFV increases intrinsic radiosensitivity, as measured by clonogenic survival assays. We hypothesize that this may be related to the drug's ability to decrease glucose uptake. Aim 1 is a phase II clinical trial of NFV in combination with RT and concurrent cisplatin chemotherapy for patients with HPV-negative, locally advanced larynx cancer, which has a poor prognosis with standard chemoradiation. Outcomes will be compared to historical controls receiving standard therapy (5-yr disease- free survival 40%) to determine whether there is any improvement with the addition of NFV. We will assess the effect of NFV on hypoxia and tumor glucose metabolism via 18F-EF5 and 18F-FDG PET/CT scanning, respectively. We will measure the effect of NFV on the PI3K/Akt pathway by assessing phosphorylation of Akt and downstream proteins in peripheral blood mononuclear cells (PBMC). Correlation between clinical outcome and response via imaging or PBMCs may allow us to predict which patients are likely to respond to NFV, and to enrich our population for a future phase III randomized trial. Our approach may lead to a novel approach to treating HNSCC with radiation, which could be extended to other cancer types treated primarily with radiation. In the subsequent aims we will investigate two aspects of NFV action that are highly relevant to the ideas being tested in the clinical trial in Aim 1. In Aim 2 we will determine whether the effect of NFV on O2 consumption is mediated by Akt inhibition and whether the drug affects mitochondria function. If we find that the O2 effect is mediated by Akt, then measuring changes in hypoxia may be a surrogate for measuring Akt inhibition in this setting. In Aim 3, we will determine whether the effect of NFV on decreasing glucose uptake is mediated by Akt inhibition, which would have implications for using 18F-FDG-PET/CT scanning to assess the efficacy of PI3K/Akt inhibitors in general. We will also investigate whether the decrease in glucose uptake in response to NFV leads to impaired anti-oxidant capacity by decreasing flux through the oxidative pentose phosphate cycle (OPPC), which we hypothesize contributes to the drug's ability to increase intrinsic radiosensitization.

描述（由申请人提供）：放射治疗（RT）通常用于治疗实体瘤~然而，即使有复杂的治疗计划和剂量输送，许多癌症的局部控制仍然很差。一个明显的例子是高风险（人乳头状瘤病毒 (HPV) 阴性）、局部晚期头颈鳞状细胞癌 (LA-HNSCC)，局部复发很常见，并导致显着的发病和死亡。与 LA-HNSCC 放疗后局部复发密切相关的因素之一是肿瘤缺氧。与此一致的是，低氧调节已被证明可以改善 HNSCC 患者的局部控制和总体生存率，特别是 HPV 阴性患者。我们在临床前模型中发现奈非那韦 (NFV)，一种具有悠久历史的 HIV 蛋白酶抑制剂 在临床中使用可减少肿瘤缺氧，从而可能增加外源性放射敏感性。此外，NFV 还增加了内在的放射敏感性，如通过克隆生存测定所测量的。我们假设这可能与该药物减少葡萄糖摄取的能力有关。 Aim 1 是一项 NFV 联合放疗和同步顺铂化疗治疗 HPV 阴性局部晚期喉癌患者的 II 期临床试验，这些患者在标准放化疗下预后不良。结果将与接受标准治疗的历史对照（5 年无病生存率 40%）进行比较，以确定添加 NFV 后是否有任何改善。我们将分别通过 18F-EF5 和 18F-FDG PET/CT 扫描评估 NFV 对缺氧和肿瘤葡萄糖代谢的影响。我们将通过评估外周血单核细胞 (PBMC) 中 Akt 和下游蛋白的磷酸化来测量 NFV 对 PI3K/Akt 通路的影响。通过影像学或 PBMC 获得的临床结果与反应之间的相关性可以让我们预测哪些患者可能对 NFV 产生反应，并为未来的 III 期随机试验丰富我们的人群。我们的 该方法可能会带来一种用放射治疗 HNSCC 的新方法，该方法可以扩展到主要用放射治疗的其他癌症类型。在后续目标中，我们将研究 NFV 作用的两个方面，这两个方面与目标 1 中临床试验中测试的想法高度相关。在目标 2 中，我们将确定 NFV 对 O2 消耗的影响是否由 Akt 抑制介导，以及药物是否影响线粒体功能。如果我们发现 O2 效应是由 Akt 介导的，那么测量缺氧的变化可能可以替代测量这种情况下的 Akt 抑制。在目标 3 中，我们将确定 NFV 对减少葡萄糖摄取的影响是否是由 Akt 抑制介导的，这对于使用 18F-FDG-PET/CT 扫描来评估 PI3K/Akt 抑制剂的总体功效具有影响。我们还将研究 NFV 引起的葡萄糖摄取减少是否会通过减少氧化戊糖磷酸循环 (OPPC) 的通量而导致抗氧化能力受损，我们假设这有助于该药物增加内在放射增敏的能力。