Development and Validation of Novel Circulating Medullary Thyroid Cancer Markers

甲状腺癌的发病率在美国每年持续增加，2010年， 被列为女性中第五大诊断癌症。在几种亚型中，甲状腺髓样癌 (MTC)占甲状腺癌病例的2 - 5%。尽管这种低频率，有一个不成比例的 与其他甲状腺癌相比，MTC的死亡人数。MTC在4年时的死亡率为50% 转移性或复发性疾病患者。在进行性转移性疾病患者中，治疗 与凡德他尼（一种酪氨酸激酶抑制剂（TKI））联合使用可改善无进展生存期，其他TKI可 也是有益的。特异性靶向RET和血管生成的凡德他尼已成为新的 有症状和疾病进展的MTC患者的护理标准。不幸的是 目前没有预测谁将对TKI治疗有反应，或确定肿瘤进展， 发展耐药性或在早期阶段监测复发的可能性。我们认为 无法识别那些在疾病过程中会更早进展的患者， 合理地，特定的TKI治疗限制了反应和益处的可能性。无细胞的测量 DNA和循环肿瘤细胞的分析已经成为与以下直接相关的生物学测量： 癌症发展、进展和对治疗的抗性。我们假设血液循环水平 DNA和/或细胞表达谱提供了总转移性肿瘤的直接和预测性测量。 潜力此外，这些测量的使用应允许药物选择的个性化、给药时间的选择和给药时间的选择。 治疗，并指导退出治疗，这将导致更好的患者结果相比， 现有的方法。满足这些需求的具体目标包括：（1）开发基于血液的检测方法 能够评估预后、转移潜力和对治疗的反应，（2）比较评估 作为治疗反应的预测因子/指标。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 已完成的研究将产生新的工具，通过增强治疗效果， 药物靶向的特异性。 相关性（参见说明）： 甲状腺癌的发病率每年继续增加，尽管新的发现已经导致了 减少大多数癌症类型。最近的研究表明，肿瘤转移和复发是由 能够接种肿瘤局部和远处再生长的细胞亚群。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 样品这些新的检测方法将用于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.