Targeting the phosphoinositide kinase chain to prevent breast cancer metastasis

靶向磷酸肌醇激酶链预防乳腺癌转移

基本信息

批准号：
7928227
负责人：
JEANNETTE KUNZ
金额：
$ 7.68万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-08 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7928227
关键词：
1-Phosphatidylinositol 4-Kinase 3-Dimensional Actins Address Adhesions Affect Agar Age-Years Anchorage-Independent Growth Animal Model Atherosclerosis Basic Science Biochemical Pathway Breast Cancer Cell Cancer Etiology Cancer Patient Cancer cell line Cell membrane Cell model Cell-Matrix Junction Cells Cessation of life Chemicals Cultured Cells Diagnosis Disease Distant Distant Metastasis Down-Regulation F-Actin Family Focal Adhesions Goals Growth Growth Factor Human Hypersensitivity In Vitro Integrins Invaded Link Lipids Malignant Neoplasms Malignant neoplasm of lung Mammary Gland Parenchyma Mammary Neoplasms Mediating Modeling Molecular Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Neoplasm Metastasis Nude Mice PIP5K2A gene Pathway interactions Patients Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphotransferases Pilot Projects Prevention Primary Neoplasm Process Production Proteins Receptor Activation Recruitment Activity Regulation Reporting Research Research Design Research Project Grants Role Signal Transduction Site Study Section Testing Therapeutic Therapeutic Intervention Tissues Tumor Cell Invasion Up-Regulation Woman Wound Healing base cancer cell cell motility chemical genetics design human disease immune function improved in vivo inhibitor/antagonist innovation malignant breast neoplasm member metastatic process migration mouse model neoplastic cell novel novel therapeutic intervention novel therapeutics overexpression phosphatidylinositol phosphate 4-kinase prevent public health relevance receptor research study response small molecule tissue culture tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the most commonly diagnosed form of cancer in women 40-55 years of age and it is the second major cause of cancer deaths behind lung cancer for all women. Metastatic breast cancer, where cancer cells spread by motile mechanisms and establish tumors at distant vital sites, is much harder to eradicate and is the primary cause of patient death from breast cancer. Understanding the molecular principles that determine the efficiency of tumor metastasis is therefore critical to the prevention and treatment of breast tumors. Traditional cancer therapeutics are aimed at preventing tumorigenesis of normal breast tissue and inhibiting growth of established cancers. However, few therapeutic strategies target cell migration and invasion, although the pathological deregulation of these processes is a major cause of morbidity associated with the disease. Cell migration and invasion are coordinately regulated by the small GTPase Rac1 and the localized production of the lipid phosphatidylinositol-4,5-bisphosphate (PI4,5P2). The hyperactivation of Rac1 signaling has been observed in many cancers, particularly in cancers of the breast, and this is directly linked to increased metastatic potential and poor patient survival. A role for PI4,5P2 signaling in cancer progression has so far not been reported. However, recent evidence described in the preliminary studies section of this proposal has established that PIPK1a, a member of the Type I phosphatidylinositol-4-phosphate kinase family, which generates PI4,5P2, is a critical regulator of cell migration and cell-matrix adhesion. We have defined a biochemical pathway in which PIPK1a mediates Rac1 activation in response to integrin and growth factor signals. Rac1, in turn, controls signaling to downstream effectors, including a second member of the PIPKI family, PIPK1b, to promote the assembly of F-actin and of focal adhesion sites necessary for migration and invasion. These results therefore establish a pathway in which PIPK1a is the pinnacle of a signaling cascade that links transmembrane receptors to the regulation of actin and focal adhesion assembly during cell motility. Because cell migration and adhesion are critical for cancer metastasis, PIPK1a may be a target for the prevention of cancer progression. The long-term goal of these studies is to validate PIPK1a as a target for therapeutic intervention in metastatic disease using tissue culture cell models and the athymic nude mouse model of breast cancer. The proposed research also involves pilot studies designed to assess the efficacy of a newly identified natural small-molecule inhibitor of PIPK1a in the control of breast cancer progression. We will use a combination of basic research, chemical genetic and in vivo approaches to systematically address the role of the PIPK1a pathway in cell migration and invasion in a 3-dimensional matrix, in anchorage-independent growth, and in cancer progression in vivo using the athymic nude mouse. The proposed research not only has the potential to impact therapeutic design to prevent breast cancer metastasis, but will also advance our understanding of signaling mechanisms that may be critical for breast cancer metastasis. PUBLIC HEALTH RELEVANCE: This research project employs cancer cell lines and mouse models of cancer metastasis to uncover the signaling mechanisms that control a cell's ability to move. The migration of cells is important for proper tissue formation, immune function and wound repair, but when aberrantly regulated can also form the basis of devastating human diseases including cancer, atherosclerosis and allergies. Our long-term goal is to better understand the signaling mechanisms that control cell migration and to use this information to develop new therapeutic approaches for the prevention of human disease.

描述（由申请人提供）：乳腺癌是 40-55 岁女性中最常见的癌症形式，也是所有女性癌症死亡的第二大原因，仅次于肺癌。转移性乳腺癌（癌细胞通过运动机制扩散并在远处重要部位形成肿瘤）更难根除，是乳腺癌患者死亡的主要原因。因此，了解决定肿瘤转移效率的分子原理对于乳腺肿瘤的预防和治疗至关重要。传统的癌症治疗旨在预防正常乳腺组织的肿瘤发生并抑制已形成的癌症的生长。然而，很少有治疗策略针对细胞迁移和侵袭，尽管这些过程的病理失调是与该疾病相关的发病的主要原因。细胞迁移和侵袭由小 GTP 酶 Rac1 和脂质磷脂酰肌醇-4,5-二磷酸 (PI4,5P2) 的局部产生协调调节。在许多癌症中，尤其是乳腺癌中，都观察到了 Rac1 信号传导的过度激活，这与转移潜力增加和患者生存率低直接相关。迄今为止，PI4、5P2 信号传导在癌症进展中的作用尚未有报道。然而，该提案的初步研究部分中描述的最新证据表明，PIPK1a（I 型磷脂酰肌醇-4-磷酸激酶家族的成员，生成 PI4,5P2）是细胞迁移和细胞基质粘附的关键调节因子。我们已经定义了一条生化途径，其中 PIPK1a 响应整合素和生长因子信号介导 Rac1 激活。 Rac1 反过来控制下游效应器的信号传导，包括 PIPKI 家族的第二个成员 PIPK1b，以促进 F-肌动蛋白和迁移和侵袭所需的粘着斑位点的组装。因此，这些结果建立了一条途径，其中 PIPK1a 是信号级联的顶峰，将跨膜受体与细胞运动过程中肌动蛋白和粘着斑组装的调节联系起来。由于细胞迁移和粘附对于癌症转移至关重要，因此 PIPK1a 可能是预防癌症进展的靶点。这些研究的长期目标是利用组织培养细胞模型和乳腺癌无胸腺裸鼠模型验证 PIPK1a 作为转移性疾病治疗干预的靶标。拟议的研究还涉及旨在评估新发现的 PIPK1a 天然小分子抑制剂在控制乳腺癌进展方面的功效的试点研究。我们将结合基础研究、化学遗传学和体内方法，利用无胸腺裸鼠。拟议的研究不仅有可能影响预防乳腺癌转移的治疗设计，而且还将增进我们对可能对乳腺癌转移至关重要的信号机制的理解。公共健康相关性：该研究项目利用癌细胞系和癌症转移的小鼠模型来揭示控制细胞移动能力的信号传导机制。细胞迁移对于正常的组织形成、免疫功能和伤口修复非常重要，但如果调节异常，也可能成为毁灭性人类疾病的基础，包括癌症、动脉粥样硬化和过敏。我们的长期目标是更好地了解控制细胞迁移的信号机制，并利用这些信息开发预防人类疾病的新治疗方法。