Development and Validation of Novel Circulating Medullary Thyroid Cancer Markers

在美国，甲状腺癌的发病率每年都在持续增加，以至于在2010年 在被诊断为癌症的女性中排名第五。在几种亚型中，甲状腺髓样癌 甲状腺癌(MTC)占甲状腺癌病例的2-5%。尽管频率很低，但仍有不成比例的 与其他甲状腺癌相比，死于甲状腺癌的人数。MTC在4年内的死亡率为50% 在转移性或复发性疾病患者中。对于进展性转移性疾病的患者，治疗 使用酪氨酸激酶抑制剂(TKI)Vandetanib可以提高无进展生存率，而其他TKI可能 也是有益的。专门针对RET和血管生成的Vandetanib已成为新的 对有症状和进展性疾病的MTC患者的护理标准。不幸的是，有一些 目前还没有预测谁会对TKI治疗有反应的措施，也没有确定肿瘤进展的方法， 在早期阶段出现耐药性或监测复发的可能性。我们相信， 无法识别哪些患者将在其病程早期进展，并无法选择 合理地说，特定的TKI治疗限制了反应和获益的潜力。无细胞数的测量 DNA和循环肿瘤细胞的图谱已经作为一种生物学措施出现，与 癌症的发展、进展和对治疗的抵抗。我们假设血液循环的水平 DNA和/或细胞表达谱提供了对总转移的直接和预测指标 潜力。此外，使用这些测量应允许个性化药物选择、时间选择 治疗，并引导退出治疗，这将导致更好的患者结果比 现有的方法。满足这些需求的具体目标包括：(1)开发基于血液的分析方法 能够评估预后、转移潜能和治疗反应，(2)比较评估 作为治疗反应的预测/指标的化验。这些目标源于广泛的MTC 治疗和研究经验，并建立在其他癌症的新兴数据财富的基础上。这个 已完成的研究将衍生出新的工具，可能通过增强 药物靶向的特异性。 相关性(请参阅说明)： 甲状腺癌的发病率每年都在增加，尽管新的发现导致了 大多数癌症类型的减少。最近的研究表明，肿瘤的转移和复发是由 一种能够种植局部和远处肿瘤再生的细胞亚群。这项建议 寻求开发新的检测方法来检测肿瘤细胞和患者血液中肿瘤细胞死亡的证据 样本。这些新的分析方法将被用来确定患者对治疗的反应。

The incidence of thyroid cancer has continued to increase each year in the United States such that in 2010 it ranked as the 5th most diagnosed cancer in women. Among several subtypes, medullary thyroid carcinoma (MTC) represents 2-5% of thyroid cancer cases. Despite this low frequency, there is a disproportionate number of deaths from MTC compared with other thyroid cancers. MTC has a 50% mortality rate at 4 years in patients with metastatic or recurrent disease. In patients with progressive metastatic disease, treatment with vandetanib, a tyrosine kinase inhibitor (TKI), improves progression-free survival, and other TKIs may also be beneficial. Vandetanib, which specifically targets RET and angiogenesis, has become the new standard of care for MTC patients with symptomatic and progressing disease. Unfortunately, there are currently no measures to predict who will respond to TKI treatment, or to identify tumor progression, development of drug resistance or monitor potential for recurrence at an early stage. We believe that the inability to identify those patients who will progress earlier in the course of their disease and to select rationally a specific TKI treatment limits potential for response and benefit. The measurement of cell-free DNA and the profiling of circulating tumor cells has emerged as a biological measure with direct relevance to cancer development, progression and resistance to therapy. We hypothesize that levels of circulating DNA and/or cellular expression profiles provides a direct and predictive measure of total metastatic potential. Furthermore, use of these measurements should allow personalization of drug choice, timing of treatment, and guide withdrawal from treatment, which will lead to better patient outcomes compared with existing approaches. The specific aims to address these needs include: (1) Develop blood-based assays capable of assessing prognosis, metastatic potential, and response to treatment, (2) Comparative evaluation of assays as predictors/indicators of therapeutic response. These aims derive from an extensive MTC treatment and research experience, and build upon an emerging wealth of data in other cancers. The completed studies will derive new tools that may offer greater therapeutic benefit through enhanced specificity of drug targeting. RELEVANCE (See instructions): Thyroid cancer incidence continues to increase annually despite the fact that new discoveries have led to reductions in most cancer types. Recent studies suggest that tumor metastasis and recurrence is driven by a subpopulation of cells that are capable of seeding local and distant regrowth of tumors. This proposal seeks to develop new assays to detect tumor cells and evidence of tumor cell death in patient blood samples. These novel assays will be used to determine patient response to treatment.