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Targeting breast cancer progression

靶向乳腺癌进展

基本信息

批准号：
10386319
负责人：
SURANGANIE DHARMAWARDHANE
金额：
$ 11.62万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-10 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10386319
关键词：
Address Affect Animals Antineoplastic Agents Apoptosis Biological Availability Body Weight Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Breast Cancer therapy Breast Epithelial Cells Cancer Etiology Cancer cell line Cardiovascular system Cell Cycle Arrest Cell Cycle Progression Cell Line Cell Surface Receptors Cell Survival Cell model Cell physiology Chemicals Clinical Trials Data Development Diagnosis Diagnostic Disease Disease model Disseminated Malignant Neoplasm Distant Drug Design Drug Kinetics Drug Targeting Ensure Extracellular Matrix Grant Grooming Guanine Nucleotide Exchange Factors Hispanics Human Human Development Immune Immune system Immunocompetent Immunocompromised Host Impairment Inbred BALB C Mice Invaded Laboratories Legal patent M cell Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Manuscripts Metastatic breast cancer Minority Molecular Mus Neoplasm Metastasis Nervous system structure New York Nonmetastatic Oncogenic Pathogenesis Postdoctoral Fellow Preparation Primary Neoplasm Prognosis Property Protein Array Protocols documentation Publishing Regulation Research Role Safety Science Series Signal Transduction Signaling Protein Site Survival Rate Testing Therapeutic Time Toxic effect Training Universities Variant Vav guanine-nucleotide exchange factor Woman analog angiogenesis anti-cancer breast cancer progression cancer cell career cdc42 GTP-Binding Protein cell motility cell type doctoral student effective therapy efficacy testing gastric cancer cell human disease improved in vivo inhibitor/antagonist malignant breast neoplasm medical schools metastasis prevention migration mortality mouse model new therapeutic target novel parent grant professor rac GTP-Binding Proteins response rho GTP-Binding Proteins screening small molecule stem targeted treatment tool tumor tumor growth

项目摘要

Metastatic disease is the primary cause of cancer mortality, but effective treatments remain elusive. Therefore, our LONG-TERM GOAL is to address the CRITICAL NEED for more targeted strategies to inhibit metastatic cancer. Metastatic cancer cells migrate away from the primary tumor and invade the extracellular matrix to enter the circulatory system and establish secondary tumors at distant sites. Accordingly, this proposal, which aims to study the role of Rho GTPases in breast cancer progression via regulation of cancer cell migration, will test novel anti metastatic cancer therapeutics. The Rho GTPases, Rac and Cdc42, are key molecular switches activated by a myriad of cell surface receptors to promote cancer cell migration/invasion, proliferation, and survival. However, there is a GAP IN KNOWLEDGE on the efficacy of Rac and Cdc42 inhibitors as anti metastatic cancer therapeutics. The OBJECTIVE in this proposal is to characterize small molecule compounds that block the interaction of Rac and/or Cdc42 with their upstream effectors, guanine nucleotide exchange factors (GEFs) in metastatic cancer. The RATIONALE for this research comes from our characterization of the Rac inhibitor EHop- 016 and the Rac/Cdc42 inhibitor MBQ-167 in cancer cell and mouse models. EHop-016 and the improved compound MBQ-167 inhibit cancer cell migration/invasion, viability, and tumor growth, metastasis, and angiogenesis in mouse models with no apparent toxicity. Using rational drug design principles garnered from our studies with these Rac/Cdc42 inhibitors, the PI’s collaborators synthesized a panel of MBQ-167 derivatives (50 compounds). The present proposal will use 6 of these compounds to test the HYPOTHESIS that MBQ- 167 and analogs have potential as anti metastatic breast cancer therapeutics. SPECIFIC AIM 1 will elucidate the mechanism of action of MBQ-167 and analogs in non-metastatic and metastatic cancer cell lines, and a normal mammary epithelial cell line. EHop-016 inhibits the activation of Rac by the oncogenic GEF Vav, but the GEFs that interact with MBQ-167 remain to be identified. Therefore, this Aim will use novel targeted mass spectrometric and protein array approaches to identify the GEFs that interact with MBQ-167 and analogs to inhibit Rac and Cdc42 activities. SPECIFIC AIM 2 will determine the efficacy and toxicity of MBQ-167 in immunocompromised and immunocompetent mouse models. Successful completion of this study will uniquely advance our understanding of metastatic cancer by establishing Rac and Cdc42 proteins as viable targets to impede metastatic breast cancer progression. This study will also result in identification of the variation in GEF expression and activity in non-metastatic and metastatic cancers and elucidate targeted therapeutic strategies. Moreover, these novel chemical probes will be available as tools to validate Rac/Cdc42 signaling as well as the function of specific GEFs in disease models. Ultimately, this study will IMPACT the development of metastasis- targeted therapies for breast cancer. The present request for a research supplement will train a minority postdoctoral fellow and enhance diversity in the biomedical sciences.

转移性疾病是癌症死亡的主要原因，但有效的治疗方法仍然难以捉摸。因此，我们的长期目标是满足对更有针对性的策略的迫切需要，以抑制转移癌症。转移性癌细胞从原发肿瘤向外迁移，侵入细胞外基质进入循环系统，并在远处建立继发性肿瘤。因此，这项旨在研究Rho GTP酶通过调节癌细胞迁移在乳腺癌进展中的作用，将测试新的抗转移癌症疗法。Rho GTP酶Rac和cdc42是被激活的关键分子开关通过大量的细胞表面受体促进癌细胞的迁移/侵袭、增殖和存活。然而，关于rac和cdc42抑制剂作为抗转移癌的有效性的认识还存在差距。治疗学。这项提议的目标是表征能够阻断细胞外信号转导通路的小分子化合物 RAC和/或CDC42与其上游效应因子鸟嘌呤核苷酸交换因子(GEF)的相互作用转移性癌。这项研究的基本原理来自我们对RAC抑制剂EHop的表征- 016和RAC/CDC42抑制剂MBq-167在癌细胞和小鼠模型中的作用。EHOP-016及其改进化合物MBQ-167抑制癌细胞的迁移/侵袭，活力，以及肿瘤的生长，转移，和在小鼠模型中血管生成没有明显的毒性。使用合理的药物设计原则，从在我们对这些RAC/Cdc42抑制剂的研究中，PI的合作者合成了一组MBQ-167衍生物 (50个化合物)。目前的提案将使用其中的6种化合物来检验MBQ- 167及其类似物具有潜在的抗转移性乳腺癌治疗作用。特定目标1将阐明MBQ-167及其类似物对非转移性和转移性癌细胞株的作用机制和一个正常的乳腺上皮细胞系。EHop-016抑制致癌的全球环境基金Vav激活RAC，但与MBQ-167相互作用的GEF仍有待确定。因此，这一目标将使用新颖的靶向质量鉴定与MBQ-167及其类似物相互作用的GEF的光谱和蛋白质阵列方法抑制RAC和CDC42的活性。特异性AIM 2将确定MBQ-167对小鼠的疗效和毒性免疫功能低下和免疫功能正常的小鼠模型。这项研究的成功完成将是独一无二的通过建立RAC和CDC42蛋白作为可行的靶点来促进我们对转移癌的理解阻止转移性乳腺癌的进展。这项研究还将导致确定全球环境基金的变化在非转移性和转移性癌症中的表达和活性，并阐明靶向治疗策略。此外，这些新的化学探针将作为工具来验证RAC/CDC42信号以及特异性GEF在疾病模型中的作用。最终，这项研究将影响转移的发展- 乳腺癌的靶向治疗。目前关于研究补充的要求将培训少数人博士后研究员和加强生物医学科学的多样性。