H-25893 ADVL0912, A PHASE 1/2 STUDY OF PF-02341066, AN ORAL SMALL MOLECULE

H-25893 ADVL0912，口服小分子 PF-02341066 的 1/2 期研究

• 批准号: 8356746
• 负责人: PATRICK THOMPSON
• 金额: $ 1.27万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356746
• 关键词: 2p23; Advanced Malignant Neoplasm; Biology; Cancer cell line; Cell Line; Chimeric Proteins; Chromosomal translocation; Clinical Research; Disease; ERBB2 gene; Epidermal Growth Factor Receptor; Erlotinib; Event; FOXO1A gene; Funding; Gene Fusion; Gene Proteins; Generations; Genes; Grant; Human; Imatinib; Inherited; Ki-1 Large-Cell Lymphoma; MET Oncogene; Malignant Neoplasms; Mediating; Molecular Target; Mutate; Mutation; NPM1 gene; National Center for Research Resources; Nerve Growth Factor Receptors; Nervous system structure; Neuroblastoma; Neuronal Differentiation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Oral; Orphan; PAX3 gene; Pathogenesis; Pathway interactions; Phase; Phosphotransferases; Play; Principal Investigator; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Protein c-kit; Receptor Protein-Tyrosine Kinases; Regulation; Research; Research Infrastructure; Resources; Rhabdomyosarcoma; Role; Signal Transduction; Solid Neoplasm; Source; Transcript; Trastuzumab; Tyrosine Kinase Domain; United States National Institutes of Health; Vascular Endothelial Growth Factors; Work; anaplastic lymphoma kinase; clinical efficacy; cost; fusion gene; inhibitor/antagonist; interest; malignant breast neoplasm; meetings; mutant; neuroblastoma cell; new therapeutic target; oncology; receptor; small molecule; successful intervention; therapeutic target; tumor; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. There is an emerging paradigm in oncology that clinical efficacy can be obtained with inhibitors directed toward oncogenic receptor tyrosine kinases (RTKs) that are mutated or otherwise dysregulated in certain tumor types. Examples of such successful intervention include imatinib in GIST with mutant c-Kit, erlotinib in NSCLC with mutant and/or amplified EGFR, trastuzumab in breast cancers with amplified HER-2, and sunitinib targeting the VHL-dependent VEGF pathway in RCC. The c-Met RTK is frequently altered or dysregulated in advanced cancers and has been implicated in tumor progression, and therefore represents an attractive novel therapeutic target. It has been shown that the Met receptor has a role in PAX3-FKHR-mediated transformation in rhabdomyosarcomas, and that MET can serve as a therapeutic target in this disease.The anaplastic lymphoma kinase gene (ALK), which has significant homology to the Met oncogene, plays a role in the pathogenesis of anaplastic large-cell lymphomas (ALCL), due to a chromosomal translocation that results in expression of an oncogenic kinase fusion protein known as NPM-ALK. ALK is an orphan tyrosine kinase transmembrane receptor with homology to neurotrophin receptors and the MET oncogene. Expression is restricted to the developing nervous system with a postulated role in the regulation of neuronal differentiation.It has recently become clear that many human cancers activate ALK signaling by creating unique oncogenic fusions of the ALK gene at 2p23 with a variety of partners through chromosomal translocation events, resulting in the generation of oncogenic ALK fusion genes and their encoded proteins. Recently, the interest in ALK biology has increased considerably, following the discovery of ALK translocations in a fraction of non-small-cell lung cancers and in other solid tumors. It is now clear that many human cancers activate ALK signaling by creating unique oncogenic fusions of ALK with a variety of partners through chromosomal translocation events. Previous work had shown that a substantial percentage of human-derived neuroblastoma cell lines express ALK transcripts and ALK protein, but no definitive role for this oncogene had been proven. We have recently discovered that activating mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) oncogene are the cause of hereditary neuroblastoma, and that these mutations can also be somatically acquired.ALK was also recently identified as a molecular target in neuroblastoma by a screen of human cancer cell lines with pharmacologic antagonists of the ALK kinase domain.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在肿瘤学中有一种新兴的范式，即针对某些肿瘤类型中突变或以其他方式失调的致癌受体酪氨酸激酶(RTK)的抑制剂可以获得临床疗效。这类成功干预的例子包括：伊马替尼联合突变c-Kit用于GIST，厄洛替尼用于非小细胞肺癌联合突变和/或扩增的EGFR，曲妥珠单抗用于乳腺癌的扩增HER-2，以及舒尼替尼靶向肾癌VHL依赖的血管内皮生长因子途径。C-Met RTK在晚期癌症中经常改变或失调，并与肿瘤的进展有关，因此是一个有吸引力的新治疗靶点。已有研究表明，Met受体在PAX3-FKHR介导的横纹肌肉瘤转化中起作用，Met可作为横纹肌肉瘤的治疗靶点。间变性淋巴瘤激酶基因(ALK)与Met癌基因有显著同源性，由于染色体易位导致癌基因融合蛋白NPM-ALK的表达，在间变性大细胞淋巴瘤(ALCL)的发病机制中发挥作用。ALK是一种孤儿酪氨酸激酶跨膜受体，与神经营养素受体和MET癌基因同源。最近的研究表明，许多人类癌症通过染色体易位事件与多种伙伴在2p23处产生独特的致癌融合来激活ALK信号，导致致癌ALK融合基因及其编码蛋白的产生。最近，随着在一小部分非小细胞肺癌和其他实体肿瘤中发现ALK易位，人们对ALK生物学的兴趣大大增加。现在清楚的是，许多人类癌症通过染色体易位事件与各种伙伴创造独特的ALK致癌融合来激活ALK信号。以前的工作表明，相当大比例的人源性神经母细胞瘤细胞系表达ALK转录本和ALK蛋白，但这种癌基因的确切作用尚未得到证实。我们最近发现，间变性淋巴瘤酪氨酸激酶域的激活突变 ALK癌基因是遗传性神经母细胞瘤的原因，这些突变也可以通过躯体获得。ALK最近也被发现是神经母细胞瘤的分子靶点，用ALK激酶域的药物拮抗剂筛选人类癌细胞系。