Optimizing Radiosensitization in Anaplastic Thyroid Cancer with Metabolic Imaging

描述（由申请人提供）：间变性甲状腺癌（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）作为实现局部区域控制的主要手段。因此，开发新型放射增敏剂对治疗这种致命疾病至关重要。由于无法在体内实时进行IR对肿瘤生物学影响的详细机制研究，新型放射增敏策略的临床实施受到了阻碍。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IR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。这种成像模式将在先前开发的甲状腺间变性癌（ATC）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的抵抗在很大程度上是由产生足够的还原等量物来中和ROS的能力驱动的。对肿瘤代谢途径的药物抑制可以降低等效水平，增强对IR的ROS生成。在这项研究中，我们将定义和完善一种基于代谢的放射增敏策略，该策略广泛适用于多种ATC细胞系。迄今为止，还不可能评估抗代谢药物对体内肿瘤减少潜力的影响，以最大限度地提高放射致敏性。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。这项研究的完成有望实现两个具体目标。首先，它将开始定义这种类型的放射增敏方法的治疗可行性。其次，它将进一步证明HP-MRS的潜力，以完善放射增敏策略的实施，并定制实体肿瘤的IR管理。在此之前，临床医生从未能够在治疗期间测量IR的有效性，并可能实时改变治疗决策。下面提出的实验是实现这种能力的关键的第一步，并为ATC和其他实体肿瘤的治疗方案设计提供了新的范例。

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.