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Targeting WASF3 to suppress metastasis

靶向 WASF3 抑制转移

基本信息

批准号：
10461806
负责人：
Eileen J Kennedy
金额：
$ 29.65万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-05 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461806
关键词：
4T1 Actins Amino Acids Binding Biological Assay Biological Process Biological Products Biology Blood Vessels Breast Breast Cancer Cell Breast Cancer Model Breast cancer metastasis Cancer Burden Cancer Patient Cells Cessation of life Clinical Clinical Management Complex Crystallization Data Development Disease Disseminated Malignant Neoplasm Distant Drug Targeting Effectiveness Event Experimental Models Extravasation Generations Genes Genetic Genetically Engineered Mouse Goals In Vitro Indolent Knowledge Lead Longevity Malignant Neoplasms Matrix Metalloproteinases Mediating Metastasis Suppression Metastatic breast cancer Minor Mission Modeling Modification Molecular Molecular Conformation Mus Mutation National Institute of General Medical Sciences Neoplasm Metastasis Operative Surgical Procedures Organ Patients Peptides Pharmaceutical Chemistry Phenotype Process Prognosis Proteins Proteolysis Public Health Regulation Relapse Research Resistance Role Signal Transduction Solubility Specificity Structure Subgroup Surface TP53 gene Technology Testing Therapeutic Therapeutic Effect Woman Xenograft Model Xenograft procedure Zebrafish aggressive breast cancer alpha helix base cancer cell conventional therapy design experimental study improved in vivo in vivo Model inhibitor innovation insight knock-down malignant breast neoplasm mortality mouse model preclinical study promoter protein complex protein function protein protein interaction prototype receptor small molecule inhibitor stapled peptide triple-negative invasive breast carcinoma tumor uptake

项目摘要

This proposal focuses on efficiently targeting critical protein-protein interactions required for WASF3 stability using stapled peptides (SPs) as a means of suppressing breast cancer cell invasion and metastasis as a proof- of-principle and may also apply broadly to other cancers that depend on WASF3 for invasion and metastasis. Women with metastatic cancers have limited treatment options and shorter lifespans compared to those with indolent tumors. Current understanding suggests that successful metastatic colonization in distant organs depends on expression of the WASF3 gene. A critical barrier to progress in improving treatment options for metastasis is the lack of conventional drugs that target the metastasis process. The goal of this project is to develop innovative and optimized targeting strategies to block WASF3 function and so inhibit invasion and metastasis in breast cancer cells. An emerging approach to suppress protein function is by targeting protein interactions essential for the function of the target using stapled peptides (SPs). SPs contain modified amino acids that maintain a stable alpha helix conformation that is resistant to proteolysis, promotes active cellular uptake and is not immunogenic. WASF3 is normally held in an autorepressed conformation through interactions with CYFIP1 and NCKAP1, which are essential components of the WASF Regulatory Complex (WRC). Knockdown of any of these proteins leads to destabilization of the WASF3 complex and suppression of invasion and metastasis. Preliminary data shows that targeting the CYFIP1-WASF3 and CYFIP-NCKAP1 interactions using SPs leads to suppression of invasion in vitro and metastasis in vivo. These prototype SPs could be used in preclinical studies but it has been shown that a wide range of modification of SPs can significantly improve their efficacy. Our objectives include optimizing these SPs to increase their solubility, specificity and stability using design and medicinal chemistry approaches to develop more potent biologics and determine the most effective derivatives that suppress metastasis. The optimized SPs will then be used in in vivo models of metastasis using a variety of mouse models of metastatic breast cancer to evaluate their ability to suppress metastasis. We will also use a zebrafish model of intravasation to test the hypothesis that WASF3, through its control of MMPs and NFkB signaling, is vital for invasion into blood vessels. We have already shown that minor modifications of active peptides increase their effectiveness in vitro. These proof-of- principle experiments demonstrate that SPs can target intracellular proteins and may serve as an effective strategy to dissect and inhibit tumor metastasis. The impact of these studies is based on the knowledge of the fundamental biology behind WASF3 function allowing the use of second-generation peptide technology to target the highly specific functions of WASF3. As a result, the development of improved therapeutic approaches for the treatment of the metastatic disease will have profound implications for the clinical management of breast (and potentially other) cancer patients.

该建议侧重于有效地针对WASF3稳定性所需的关键蛋白质-蛋白质相互作用使用装订多肽(SPS)作为抑制乳腺癌细胞侵袭和转移的手段作为证据- 也可能广泛适用于依赖WASF3进行侵袭和转移的其他癌症。与患有转移性癌症的女性相比，女性转移性癌症的治疗选择有限，寿命更短。惰性肿瘤。目前的理解表明，在远处器官中成功的转移定植这取决于WASF3基因的表达。在改善治疗方案方面取得进展的关键障碍转移是缺乏针对转移过程的常规药物。这个项目的目标是开发创新和优化的靶向策略，以阻断WASF3功能，从而抑制入侵和乳腺癌细胞的转移。一种新的抑制蛋白质功能的方法是通过靶向蛋白质使用已装订的多肽(SP)对靶标的功能至关重要的相互作用。SP含有改性的氨基保持稳定的α螺旋构象的酸，可防止蛋白质分解，促进细胞活跃摄取，不具有免疫原性。WASF3通常以自动抑制的构象形式通过与CYFIP1和NCKAP1的相互作用，这两个基因是WASF调控复合体的重要组成部分 (WRC)。这些蛋白质中的任何一种的敲除都会导致WASF3复合体的不稳定和抑制侵袭和转移。初步数据显示，靶向CYFIP1-WASF3和CYFIP-NCKAP1 使用SPS的相互作用可以抑制体外侵袭和体内转移。这些原型SP 可以用于临床前研究，但已经表明，对SPS进行广泛的修饰可以显著提高了它们的疗效。我们的目标包括优化这些SP以增加它们的溶解度，特异性和稳定性使用设计和药物化学方法开发更有效的生物制剂和确定最有效的抑制转移的衍生物。然后，优化的SP将用于体内转移模型用多种小鼠转移性乳腺癌模型评价其能力以抑制肿瘤转移。我们还将使用斑马鱼血管内凝血的模型来检验这一假设 WASF3通过控制MMPs和NFkB信号通路，对血管的侵袭起着至关重要的作用。我们有已经证明，对活性多肽进行微小的修饰可以提高它们在体外的有效性。这些证据- 原理实验表明，SPS可以靶向胞内蛋白，并可能作为一种有效的解剖和抑制肿瘤转移的策略。这些研究的影响是基于对 WASF3功能背后的基础生物学允许使用第二代多肽技术瞄准WASF3高度特定的功能。因此，改进的治疗方法的发展转移性疾病的治疗方法将对临床产生深远的影响。乳腺癌(和潜在的其他)癌症患者的管理。