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%。目前的治疗模式依赖于电离辐射（IR）作为实现局部控制的主要手段。因此，开发新的放射增敏剂在这种致命疾病的管理中至关重要。新的放射增敏策略的临床实施受到阻碍，因为无法在体内真实的时间内进行IR对肿瘤生物学影响的详细机制研究。我们最近已经证明，超极化磁共振波谱（HP-MRS）可用于检测干扰肿瘤代谢后，有针对性的药理学抑制和暴露于IR。在这里，我们建议使用HP-MRI来评估肿瘤的放射增敏作用的抗代谢药物。这种成像方式将在以前开发的甲状腺未分化癌（ATC）的综合临床前模型的背景下使用。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的抗性在很大程度上由产生足够的还原当量以中和ROS的能力驱动。肿瘤代谢途径的药理学抑制可以降低还原当量水平，并增强ROS的产生，以响应IR。在这项研究中，我们将定义和完善代谢为基础的放射增敏策略，广泛适用于多种ATC细胞系。到目前为止，还不可能以最大化放射增敏的方式评价抗代谢药物对体内肿瘤减少潜力的影响。我们首次提出使用HP-MRS来确定和优化基于代谢的放射增敏策略的有效性。这项研究的完成预计将实现两个具体目标。首先，它将开始确定这种放射增敏方法的治疗可行性。第二，它将进一步证明HP-MRS的潜力，以完善一般的放射增敏策略的实施和定制的IR t实体瘤的管理。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