Development and Validation of Novel Circulating Medullary Thyroid Cancer Markers

新型循环甲状腺髓样癌标志物的开发和验证

• 批准号: 8588548
• 负责人: GILBERT J. COTE
• 金额: $ 43.72万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588548
• 关键词: Address; Adverse effects; Archives; Biological; Biological Assay; Blood; Blood Circulation; Blood Vessels; Blood specimen; Cancer Center; Cell Death; Cell Line; Cells; Cessation of life; Characteristics; Clinical; DNA; DNA Fingerprinting; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Distant; Distant Metastasis; Documentation; Drug Approval; Drug Monitoring; Drug Targeting; Drug resistance; Ensure; Evaluation; Frequencies; Goals; Growth; Heterogeneity; Incidence; Individual; Inherited; Instruction; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of thyroid; Measurement; Measures; Messenger RNA; Molecular Profiling; Monitor; Mutation; Neoplasm Circulating Cells; Neoplasm Metastasis; Newly Diagnosed; Ohio; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Predictive Value; Prevalence; Progression-Free Survivals; Property; Proto-Oncogenes; Recording of previous events; Recurrence; Recurrent disease; Research; Resistance; Risk; Sampling; Side; Specificity; Stage at Diagnosis; Staging; Stem cells; Structure of thyroid parafollicular cell; System; Systemic Therapy; TNFRSF5 gene; The Sun; Therapeutic; Thyroid Gland; Thyroidectomy; Time; Tumor stage; Tyrosine Kinase Inhibitor; United States; Universities; Validation; Withdrawal; Woman; angiogenesis; base; cancer diagnosis; cancer therapy; cancer type; cohort; comparative; experience; improved; medullary thyroid carcinoma; mortality; neoplastic cell; next generation; novel; outcome forecast; prophylactic; receptor; response; standard of care; therapy resistant; tool; treatment response; treatment strategy; tumor; tumor growth; tumor progression

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.

在美国，甲状腺癌的发病率逐年增加，2010 年 被列为女性中第五大确诊癌症。在多种亚型中，甲状腺髓样癌 (MTC) 占甲状腺癌病例的 2-5%。尽管频率较低，但存在不成比例的情况 与其他甲状腺癌相比，MTC 导致的死亡人数。 MTC 4 年死亡率为 50% 患有转移性或复发性疾病的患者。对于患有进展性转移性疾病的患者，治疗 与酪氨酸激酶抑制剂 (TKI) 凡德他尼联合使用可改善无进展生存期，而其他 TKI 可能 亦有裨益。 Vandetanib 专门针对 RET 和血管生成，已成为新的治疗药物 有症状和疾病进展的 MTC 患者的护理标准。不幸的是，有 目前没有措施可以预测谁会对 TKI 治疗产生反应，或确定肿瘤进展， 耐药性的发展或在早期监测复发的可能性。我们相信 无法识别那些在病程早期会进展的患者并选择 合理地，特定的 TKI 治疗限制了潜在的反应和获益。游离细胞的测量 DNA 和循环肿瘤细胞的分析已成为一种与以下疾病直接相关的生物学测量方法： 癌症的发生、进展和对治疗的抵抗。我们假设循环水平 DNA 和/或细胞表达谱提供了总转移的直接和预测性测量 潜在的。此外，这些测量的使用应该允许药物选择、用药时间的个性化。 治疗，并指导退出治疗，与相比，这将带来更好的患者结果 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、转移潜力和治疗反应，（2）比较评价 作为治疗反应的预测因子/指标的测定。这些目标源自广泛的 MTC 治疗和研究经验，并建立在其他癌症的新兴数据财富之上。这 已完成的研究将得出新的工具，可以通过增强的治疗效果提供更大的治疗效果 药物靶向的特异性。 相关性（参见说明）： 尽管新发现导致甲状腺癌发病率每年持续增加 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以下因素驱动的： 能够播种局部和远处肿瘤再生的细胞亚群。这个提议 寻求开发新的检测方法来检测患者血液中的肿瘤细胞和肿瘤细胞死亡的证据 样品。这些新颖的测定将用于确定患者对治疗的反应。