Migrastatin Analogues and Inhibition of Tumor Metastasis

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，预防肿瘤转移将显著提高癌症患者的生存率，允许更多的副作用较少的适度放疗或化疗，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。在这个应用中，我们关注一组新的小分子，米曲司汀类似物。我们已经证明，这些小分子是转移的肿瘤细胞迁移的有效抑制者，但不是正常的原代细胞。我们已经在小鼠模型中证明了其中两个米非司汀类似物减少了小鼠乳腺肿瘤的转移。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/预防的米非司汀类似物。我们在这项申请中提出了三个具体目标。在具体目标1中，我们将重点研究米非司汀类似物抑制肿瘤细胞迁移的分子机制。在特定的目标2中，我们将研究米非司他丁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，我们将研究米曲斯汀类似物对免疫受损裸鼠体内人乳腺癌细胞转移的影响。本研究的成功将为肿瘤的治疗，特别是肿瘤转移的预防提供一种新的治疗方法。公共卫生相关性：该提案调查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害怕的事情。不幸的是，乳腺癌一旦转移，目前还没有治愈的方法。因此，对转移性(晚期)乳腺癌的新治疗方法有巨大的需求。由于肿瘤细胞迁移是乳腺癌转移的关键，细胞迁移抑制药可作为治疗乳腺癌的新药。米曲斯汀的类似物前景看好。

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.