Synthetic Regulators of Tyrosine Protein Kinases

描述(由申请人提供)：识别肿瘤发生和转移的生化基础的传统策略依赖于对上调(或下调)基因和蛋白质的搜索。虽然这种方法已经导致了挽救生命的发现，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的男性最终会死于其他疾病。前列腺癌是一种典型的缓慢增长的疾病。对于这些患者来说，治疗是不必要的，而且往往比疾病更糟糕。然而，相当大一部分前列腺癌患者将发现自己面临着难以治愈的转移性疾病：每年有近3万名美国男性死于前列腺癌。在诊断时，由于缺乏明确的生化标志物，就不可能有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，传统的生物标记物可能根本不存在。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，转移潜能被认为与转移性癌细胞系和患者来源的肿瘤细胞所表现出的侵袭性、蛋白酶活性突起的形成有关。内脏足以一种类似砍刀的方式促进细胞外基质的分解，这是随后入侵周围组织所必需的行为。蛋白酪氨酸激酶Src对于内侧足纲的形成和功能是充分和必要的。然而，还没有明确地评估在不定足动物体内的Src激酶活性，也没有确定其局部活性作为全球Src含量的函数。后者位于最近形成的关于转移潜能的生化基础的假说的核心：促进细胞侵袭的信号通路的局部激发和全局抑制。简而言之，癌症的侵袭性可能是细胞内环境空间聚焦区域高信号活性的结果。一种新的成像试剂，具有高空间(和时间)分辨率的特性，将准备应对癌症研究方向的这种意想不到的变化。 公共卫生相关性：这项研究中将要开发的试剂最终可能使在癌症诊断时快速确定转移潜力成为可能。

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.