Novel Pathways for Bcr-Abl transformation

Bcr-Abl 转化的新途径

• 批准号: 8069202
• 负责人: IAN P WHITEHEAD
• 金额: $ 27.09万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-03 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069202
• 关键词: Agreement; Allogenic; Animals; Apoptosis; Binding; Binding Sites; Biology; Cell Nucleus; Cells; Chimeric Proteins; Chronic Myeloid Leukemia; Clinical; Complement; Complex; Cytoplasm; DH Domain; Development; Disease; Docking; Drug Design; ERCC3 gene; Endosomes; Epidermal Growth Factor Receptor; Exhibits; Funding; Goals; Health; Hematopoietic; Imatinib; Intervention; Laboratories; Malignant Neoplasms; Maps; Mediating; Modality; Modeling; Mutation; Nuclear; Nuclear Matrix; Nucleotide Excision Repair; Oncogene Proteins; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Property; Protein Tyrosine Kinase; Proteins; Radiation; Repair Complex; Residual Neoplasm; Resistance; Resistance development; Role; Signal Transduction; Site; Sorting - Cell Movement; Stem cell transplant; Testing; Transcript; Ubiquitin; base; bcr-abl Fusion Proteins; c-myc Genes; cancer therapy; clinical remission; driving force; inhibitor/antagonist; mutant; novel; novel strategies; overexpression; protein expression; response; rho; success; transcription factor TFIIH; treatment strategy; tumorigenic

DESCRIPTION (provided by applicant): Numerous animal studies have demonstrated that the fusion protein p210 Bcr-Abl is the causative agent of Chronic Myelogenous Leukemia (CML), and pharmacological inhibitors (such as imatinib) that target this molecule produce effective, durable responses in many patients. Imatinib targets a tyrosine kinase activity contained within the Abl sequences that is considered to be the principle driving force behind CML. Although the success of imatinib has validated rational drug design in cancer therapy, two clinical issues are emerging in the treatment of CML. First, patients are developing resistance to imatinib by acquiring mutations within the kinase domain (acquired resistance). Second, and probably more problematic, over 95% of patients still have p210 Bcr-Abl positive cells, even after 12 months of imatinib treatment (minimal residual disease). Whether or not acquired resistance and minimal residual disease are mechanistically related is unclear, but both problems highlight the need to develop complementary inhibitors, with different modalities, that can target additional functions of p210 Bcr-Abl. Although the tumorigenic properties of p210 Bcr-Abl can be primarily attributed to the Abl-encoded kinase activity, numerous studies have determined that there are also domains present within the Bcr sequences that are required to support oncogenic activity. Although poorly characterized, these domains are intriguing since they represent unexploited targets for pharmacological intervention. In the previous funding period, our laboratory as been exploring the hypothesis that the characterization of Bcr- encoded activities will identify viable new targets for p210 Bcr-Abl inhibition. Three such activities have now been identified. First, it has been determined that the RhoGEF domain, which is autoinhibited in Bcr, is constitutively activated in p210 Bcr-Abl. Mutations that eliminate this activity in p210 Bcr-Abl exhibit diminished transforming activity in cell- and animal-based models suggesting that this domain may be required for CML. Second, it has been determined that Bcr is a regulatory component of the endosomal sorting pathway, and that this pathway is disrupted by overexpression of p210 Bcr-Abl in hematopoietic cells. This represents a novel, and completely unexplored aspect of p210 Bcr-Abl biology, which undoubtedly will be relevant to CML. Finally, it has been determined that Bcr has a nuclear function through which it can regulate levels of protein expression. This includes the c-Myc oncoprotein which is known to contribute to CML. Bcr-Abl regulates c- Myc through binding to XPB, and disruption of this interaction is also associated with diminished transforming activity in cell- and animal-based models. In this continuation application these activities will be characterized in the context of hematopoietic cells, and it will be determined whether they are viable targets for p210 Bcr-Abl inhibition. For this analysis, p210 Bcr-Abl mutants have been generated that are impaired in these activities, and which can be evaluated in cell- and animal-based models for CML. PUBLIC HEALTH RELEVANCE: Imatinib is a pharmacological inhibitor that causes clinical remission in many patients with Chronic Myelogenous Leukemia. However, imatinib controls rather than cures the disease, and many patients develop resistance to the treatment. Thus, the focus of this proposal is the development of novel approaches and inhibitors that can be used to complement imatinib treatment.

描述(申请人提供)：大量动物研究表明，融合蛋白p210 bcr-abl是慢性粒细胞白血病(CML)的病原体，针对该分子的药物抑制剂(如伊马替尼)在许多患者中产生有效、持久的反应。伊马替尼的靶点是Abl序列中包含的一种酪氨酸激酶活性，这被认为是慢性粒细胞白血病背后的主要驱动力。虽然伊马替尼的成功验证了癌症治疗中合理的药物设计，但在慢性粒细胞白血病的治疗中出现了两个临床问题。首先，患者通过获得激活域内的突变(获得性耐药性)而对伊马替尼产生耐药性。其次，可能更有问题的是，即使在伊马替尼治疗(微小残留疾病)12个月后，超过95%的患者仍有p210 bcr-abl阳性细胞。获得性耐药和微小残留病是否在机制上相关尚不清楚，但这两个问题都突显了开发补充抑制剂的必要性，这些抑制剂具有不同的模式，可以靶向p210 bcr-Abl的额外功能。虽然p210 bcr-abl的致癌特性主要归因于abl编码的激酶活性，但许多研究已经确定，在bcr序列中也存在支持致癌活性所需的结构域。尽管描述不佳，但这些领域很耐人寻味，因为它们代表了药物干预的未开发目标。在之前的资助期间，我们的实验室一直在探索这样一种假设，即对BCR编码的活性的表征将识别出可行的新靶点来抑制p210 BCR-Abl。现已确定了三项此类活动。首先，已经确定在bcr中自我抑制的Rhogef结构域在p210 bcr-Abl中被结构性激活。在基于细胞和动物的模型中，消除p210bcr-Abl中这种活性的突变显示出转化活性降低，这表明CML可能需要这个结构域。第二，已经确定bcr是内体分选途径的调节成分，并且这一途径被造血细胞中p210 bcr-Abl的过表达所干扰。这代表了p210 bcr-abl生物学的一个全新的、完全未被探索的方面，这无疑将与CML相关。最后，已经确定bcr具有核功能，通过它可以调节蛋白质表达水平。这包括已知对慢性粒细胞白血病有贡献的c-Myc癌蛋白。BCR-Abl通过与XPB结合来调节c-Myc，这种相互作用的中断也与细胞和动物模型中转化活性的降低有关。在这一后续应用中，将在造血细胞的背景下表征这些活性，并将确定它们是否为p210 bcr-abl抑制的可行靶点。对于这一分析，已经产生了在这些活动中受损的p210 bcr-abl突变体，并且可以在慢性粒细胞白血病的细胞和动物模型中进行评估。公共卫生相关性：伊马替尼是一种药理抑制剂，可导致许多慢性粒细胞白血病患者的临床缓解。然而，伊马替尼控制而不是治愈疾病，许多患者对这种治疗产生抵抗力。因此，该提案的重点是开发可用于补充伊马替尼治疗的新方法和抑制剂。