Optimizing Radiosensitization in Anaplastic Thyroid Cancer with Metabolic Imaging

通过代谢成像优化甲状腺未分化癌的放射增敏

• 批准号: 8879068
• 负责人: STEPHEN Y LAI
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879068
• 关键词: Accounting; Acute; Animal Model; Cancer cell line; Cell Death; Cessation of life; Clinical; Data; Detection; Development; Disease; Dose; Effectiveness; Exposure to; Generations; Goals; Health; Image; In Vitro; Intervention; Ionizing radiation; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Malignant neoplasm of thyroid; Measures; Metabolic; Metabolic Pathway; Modeling; Monitor; Natural regeneration; Pathway interactions; Pharmaceutical Preparations; Pre-Clinical Model; Proteins; Radiation-Induced Change; Radiation-Sensitizing Agents; Radiosensitization; Reactive Oxygen Species; Regimen; Resistance; Solid Neoplasm; Specificity; Testing; Therapeutic; Thyroid carcinoma; Time; Translations; Treatment Protocols; Tumor Biology; anaplastic thyroid cancer; base; design; dosage; effective therapy; human disease; imaging modality; improved; in vivo; innovation; neoplastic cell; novel; pre-clinical; prevent; radiation effect; radiosensitizing; research study; response; tumor; tumor metabolism

DESCRIPTION (provided by applicant): Anaplastic thyroid cancer (ATC) is an aggressive malignancy, which accounts for approximately 50% of all thyroid cancer related deaths. Current treatment paradigms rely on ionizing radiation (IR) as a primary means of achieving locoregional control. As such, development of novel radiosensitizing agents is of crucial importance in the management of this deadly disease. Clinical implementation of novel radiosensitizing strategies has been hampered by an inability to perform detailed mechanistic studies of IR effects on tumor biology in vivo in real time. We have recently demonstrated that hyperpolarized magnetic resonance spectroscopy (HP-MRS) can be used to detect perturbations in tumor metabolism following targeted pharmacologic inhibition and exposure to IR. Here we propose to use HP-MRI to evaluate tumor response to the radiosensitizing effects of anti-metabolic drugs. This imaging modality will be utilized in the context of a previously developed integrated preclinical model of anaplastic thyroid carcinoma (ATC). Ionizing radiation (IR) induces tumor cell death primarily through the formation of reactive oxygen species (ROS). Tumor cell resistance to IR is driven in large part by the ability to generate sufficient reducing equivalents to neutralize ROS. Pharmacologic inhibition of tumor metabolic pathways can decrease reducing equivalent levels and potentiate ROS generation in response to IR. In this study we will define and refine a metabolically based radiosensitization strategy broadly applicable across multiple ATC cell lines. To date it has not been possible to evaluate the effects of anti-metabolic agents on tumor reducing potential in vivo in a manner designed to maximize radiosensitization. For the first time, we propose to use HP-MRS to ascertain and optimize the effectiveness of a metabolically based radiosensitization strategy. Completion of this study is expected to achieve two specific goals. First, it will begin to define the therapeutic viability of this type of a radiosensitizatio approach. Second, it will further demonstrate the potential of HP-MRS to refine the implementation of radiosensitization strategies in general and to tailor the administration of IR t solid tumors. Never before have clinicians been able to measure IR effectiveness during treatment and potentially alter treatment decisions in real-time. The experiments proposed below represent a critical first step towards attaining that ability and providing a new paradigm for therapeutic regimen design in ATC and other solid tumors.

描述（由申请人提供）：甲状腺未分化癌 (ATC) 是一种侵袭性恶性肿瘤，约占所有甲状腺癌相关死亡的 50%。当前的治疗范例依赖电离辐射（IR）作为实现局部控制的主要手段。因此，开发新型放射增敏剂对于治疗这种致命疾病至关重要。由于无法实时对 IR 对体内肿瘤生物学的影响进行详细的机制研究，新型放射增敏策略的临床实施受到阻碍。我们最近证明，超极化磁共振波谱 (HP-MRS) 可用于检测靶向药物抑制和暴露于红外后肿瘤代谢的扰动。在这里，我们建议使用 HP-MRI 来评估肿瘤对抗代谢药物放射增敏作用的反应。这种成像方式将用于先前开发的未分化甲状腺癌（ATC）的综合临床前模型。电离辐射（IR）主要通过活性氧（ROS）的形成诱导肿瘤细胞死亡。肿瘤细胞对IR的抵抗在很大程度上是由产生足够的还原当量来中和ROS的能力驱动的。肿瘤代谢途径的药物抑制可以降低还原当量水平并增强响应 IR 的 ROS 生成。在这项研究中，我们将定义和完善一种广泛适用于多种 ATC 细胞系的基于代谢的放射增敏策略。迄今为止，还不可能以最大限度地提高放射增敏作用的方式评估抗代谢药物对体内肿瘤减少潜力的影响。我们首次建议使用 HP-MRS 来确定和优化基于代谢的放射增敏策略的有效性。完成这项研究预计将实现两个具体目标。首先，它将开始确定此类放射增敏方法的治疗可行性。其次，它将进一步证明 HP-MRS 在完善一般放射增敏策略的实施和定制 IR t 实体瘤的给药方面的潜力。临床医生以前从未能够在治疗期间测量 IR 有效性并可能实时改变治疗决策。下面提出的实验代表了实现这种能力的关键的第一步，并为 ATC 和其他实体瘤的治疗方案设计提供了新的范例。

项目成果

Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model.

• DOI: 10.1158/1535-7163.mct-15-0217
• 发表时间: 2015-12
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Sandulache VC;Chen Y;Skinner HD;Lu T;Feng L;Court LE;Myers JN;Meyn RE;Fuller CD;Bankson JA;Lai SY
• 通讯作者: Lai SY

Metabolic interrogation as a tool to optimize chemotherapeutic regimens.

代谢询问作为优化化疗方案的工具。

• DOI: 10.18632/oncotarget.15186
• 发表时间: 2017
• 期刊: Oncotarget
• 作者: Sandulache,VladC;Chen,Yunyun;Feng,Lei;William,WilliamN;Skinner,HeathD;Myers,JeffreyN;Meyn,RaymondE;Li,Jinzhong;Mijiti,Ainiwaer;Bankson,JamesA;Fuller,CliftonD;Konopleva,MarinaY;Lai,StephenY
• 通讯作者: Lai,StephenY