Synthetic Regulators of Tyrosine Protein Kinases

酪氨酸蛋白激酶的合成调节剂

• 批准号: 8234643
• 负责人: DAVID S. LAWRENCE
• 金额: $ 28.81万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234643
• 关键词: Address; American; Androgens; Area; Behavior; Biochemical; Biochemical Markers; Biological Markers; Breeding; Cancer Patient; Cancer cell line; Cell Line; Cells; Diagnosis; Disease; Disseminated Malignant Neoplasm; Environment; Extracellular Matrix; Funding; Gene Proteins; Heart; Heterogeneity; Image; Lead; Life; Light; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic to; Nature; Neoplasm Metastasis; Patients; Peptide Hydrolases; Peptides; Property; Prostate; Protein Tyrosine Kinase; Reagent; Relative (related person); Resolution; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Subcellular structure; Time; Tissues; Treatment Protocols; anticancer research; base; cancer diagnosis; inhibitor/antagonist; kinase inhibitor; men; molecular imaging; neoplastic cell; outcome forecast; response; sensor; spatiotemporal; src-Family Kinases; tumorigenesis

DESCRIPTION (provided by applicant): Conventional strategies for identifying the biochemical basis of tumorigenesis and metastasis rely upon the search for up- (or down-) regulated genes and proteins. Although this approach has lead to life-saving discoveries, many areas of cancer diagnosis, treatment, and prognosis remain intractable. For example, the vast majority of men diagnosed with prostate cancer, a typically slow growing disease, will eventually die from some other disorder. For these patients, treatment is unnecessary and often worse than the disease. However, a significant fraction of prostate cancer patients will find themselves dealing with the difficult-to-cure metastatic form of the disease: nearly 30,000 American men die from prostate cancer every year. The absence of clear-cut biochemical markers precludes a satisfactory treatment protocol at the time of diagnosis. Indeed, conventional biomarkers may simply not exist given the complexity and heterogeneity of prostate cancer. Is it possible to identify and image subcellular structures that are barometers of metastatic disease in general and the deadly androgen-independent form of prostate cancer in particular? Recently, metastatic potential has been linked to the formation of invadopodia, protease-active protrusions displayed by metastatic cancer cell lines and by patient-derived tumor cells. Invadopodia promote the breakdown of the extracellular matrix in a machete-like fashion, a behavior required for subsequent invasion of surrounding tissue. The protein tyrosine kinase Src is both sufficient and necessary for invadopodia formation and function. However, Src kinase activity within invadopodia has not been explicitly assessed nor has its localized activity been determined as a function of global Src content. The latter lies at the heart of a recently formulated hypothesis concerning the biochemical basis of metastatic potential: local-excitation, global-inhibition of signaling pathways that promote cell invasion. In short, cancer aggressiveness may be a consequence of high signaling activity in spatially focused regions of the intracellular environment. A new breed of imaging reagents, with properties that display a high degree of spatial (and temporal) resolution, will be prepared to address this unexpected change in direction of cancer research. PUBLIC HEALTH RELEVANCE: The reagents to be developed in this study may ultimately make it feasible to rapidly determine metastatic potential at the time of cancer diagnosis.

描述（由申请人提供）：确定肿瘤发生和转移的生化基础的传统策略依赖于寻找上调（或下调）调控的基因和蛋白质。尽管这种方法带来了挽救生命的发现，但癌症诊断、治疗和预后的许多领域仍然难以解决。例如，绝大多数被诊断患有前列腺癌（一种典型的生长缓慢的疾病）的男性最终会死于其他疾病。对这些病人来说，治疗是不必要的，而且往往比疾病本身更糟糕。然而，很大一部分前列腺癌患者会发现自己面临着难以治愈的转移性疾病：每年有近3万美国男性死于前列腺癌。在诊断时，缺乏明确的生化标记物妨碍了令人满意的治疗方案。事实上，考虑到前列腺癌的复杂性和异质性，传统的生物标志物可能根本不存在。是否有可能识别和成像亚细胞结构，这些亚细胞结构通常是转移性疾病的晴雨表，特别是致命的雄激素非依赖性前列腺癌？最近，转移潜能与侵过性突起的形成有关，蛋白酶活性突起在转移癌细胞系和患者源性肿瘤细胞中表现出来。侵入性足促进细胞外基质以一种类似砍刀的方式分解，这是随后侵入周围组织所必需的行为。蛋白酪氨酸激酶Src对于侵殖虫的形成和功能是充分和必要的。然而，invadopodia内的Src激酶活性尚未被明确评估，其局部活性也未被确定为全局Src含量的函数。后者是最近制定的关于转移潜能的生化基础的假设的核心：局部激发，促进细胞侵袭的信号通路的全局抑制。简而言之，癌症侵袭性可能是细胞内环境空间聚焦区域高信号活动的结果。一种新型成像试剂，具有显示高度空间（和时间）分辨率的特性，将准备好应对癌症研究方向的这种意想不到的变化。