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Migrastatin Analogues and Inhibition of Tumor Metastasis

米格拉他汀类似物及其对肿瘤转移的抑制

基本信息

批准号：
8111229
负责人：
Xin-Yun Huang
金额：
$ 33.48万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2009-09-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111229
关键词：
Actins Address Adverse effects Animal Model Biochemical Biochemistry Breast Cancer Cell Breast Cancer Treatment Bundling Cancer Patient Cause of Death Cells Cellular biology Chemical Actions Chemicals Clinical Trials Complex Disseminated Malignant Neoplasm Down-Regulation Epithelial Cells Evaluation Family Fright Health Human Immune Malignant Neoplasms Mammary Neoplasms Mammary gland Molecular Molecular Biology Mus Neoplasm Metastasis Nude Mice Pharmaceutical Preparations Prevention Proteins RNA Interference Radiation Recurrence Research Roentgen Rays Role Staging Structure Survival Rate Technology Therapeutic Toxic effect United States Food and Drug Administration Validation analog base cancer cell cancer therapy cell motility chemotherapy drug candidate fascin inhibitor/antagonist malignant breast neoplasm migrastatin migration mouse model neoplastic cell novel novel therapeutics pre-clinical programs public health relevance small molecule structural biology success tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Tumor metastasis is the major cause of death of cancer patients. Thus, prevention of tumor metastasis will significantly increase the survival rate of cancer patients, allow more moderate radiation or chemotherapy with less side- effects, and control the progression of tumors. One critical step of tumor metastasis is tumor cell migration and invasion. In this application, we focus on a new group of small molecules, the migrastatin analogues. We have shown that these small molecules are potent inhibitors of the migration of metastatic tumor cells, but not normal primary cells. We have shown that two of these migrastatin analogues reduced mouse breast tumor metastasis in a mouse model. We will perform preclinical discovery research and eventually develop these migrastatin analogues for cancer treatment/prevention. We have proposed three specific aims in this application. In the specific aim 1, we will focus on the molecular mechanism by which migrastatin analogues inhibit tumor cell migration. In the specific aim 2, we will examine the role of the target protein of migrastatin analogues in breast tumor cell migration, invasion, and metastasis. In the specific aim 3, we will investigate the effect of migrastatin analogues on the metastasis of human breast cancer cells in immune-compromised nude mice. The success of our study will provide a new therapeutic for cancer treatment, specifically for metastasis prevention. PUBLIC HEALTH RELEVANCE: The proposal investigates potential therapeutics for treatment of metastatic breast cancer. The spread or recurrence of breast cancer is every breast cancer patient's worst fear. Unfortunately, there is currently no curative treatment for breast cancer once it has metastasized. Therefore, there is a tremendous need for new treatments for metastatic (advanced stage) breast cancer. Since tumor cell migration is essential for breast tumor metastasis, cell migration inhibitors can be developed as new drugs to treat breast cancers. The migrastatin analogues hold much promise.

描述（申请人提供）：肿瘤转移是癌症患者死亡的主要原因。因此，预防肿瘤转移将显着提高癌症患者的生存率，允许更温和且副作用更少的化疗，并控制肿瘤的进展。肿瘤转移的关键步骤之一是肿瘤细胞的迁移和侵袭。在此应用中，我们关注一组新的小分子，即迁移他汀类似物。我们已经证明，这些小分子是转移性肿瘤细胞迁移的有效抑制剂，但不是正常原代细胞。我们已经证明，其中两种迁移他汀类似物可以在小鼠模型中减少小鼠乳腺肿瘤转移。我们将进行临床前发现研究，并最终开发这些用于癌症治疗/预防的迁移他汀类似物。我们在此应用中提出了三个具体目标。在具体目标1中，我们将重点研究migrastatin类似物抑制肿瘤细胞迁移的分子机制。在具体目标2中，我们将研究migrastatin类似物的靶蛋白在乳腺肿瘤细胞迁移、侵袭和转移中的作用。在具体目标3中，我们将研究migrastatin类似物对免疫受损裸鼠体内人乳腺癌细胞转移的影响。我们研究的成功将为癌症治疗，特别是预防转移提供新的疗法。公共卫生相关性：该提案研究了治疗转移性乳腺癌的潜在疗法。乳腺癌的扩散或复发是每个乳腺癌患者最担心的事情。不幸的是，目前还没有针对转移的乳腺癌的治愈方法。因此，非常需要针对转移性（晚期）乳腺癌的新疗法。由于肿瘤细胞迁移对于乳腺肿瘤转移至关重要，因此可以开发细胞迁移抑制剂作为治疗乳腺癌的新药。米格拉他汀类似物有着广阔的前景。