INHIBITING SURFACE HSP90 TO LIMIT METASTASIS

抑制表面 HSP90 以限制转移

• 批准号: 7095887
• 负责人: Daniel G. Jay
• 金额: $ 28.38万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095887
• 关键词: SCID mouse; antineoplastics; breast neoplasms; clinical research; heat shock proteins; human tissue; metastasis; molecular chaperones; neoplasm /cancer chemotherapy; prognosis; protein structure function; therapy design /development

DESCRIPTION (provided by applicant): The vast majority of breast cancer-related deaths are due to secondary tumors after metastasis. There is currently no effective therapy to limit metastasis. Our long term objective is to develop new therapies that reduce cancer invasion, a critical first step in metastasis. This proposal is based on our observations that a novel extracellular form of the molecular chaperone hsp90a is required for cancer invasion by the activation of the matrix metalloproteinase MMP2. Hsp90 has been implicated in cancer and hsp90 inhibitors with anti-tumor activity are currently in clinical trials. These drugs may be problematic in that they interfere with the many intracellular functions of hsp90. Our findings suggest our main hypothesis that inhibiting extracellular hsp90a will decrease invasion and thus limit metastasis. This presents an opportunity for novel anti-cancer therapy by inhibiting invasion without interfering with the myriad intracellular functions of hsp90. To support this idea, we will address three specific aims. We will determine the mechanism of how hsp90a functions on the outside of cancer cells (Aim 1). We will then use this information to develop and test extracellular hsp90 inhibitors (Aim 2). We already have one impermeant hsp90 inhibitor in hand and several candidates for neutralizing single chain antibodies from our collaborators at NCI and Xerion Pharmaceuticals. Finally, we will test the best of these inhibitors of extracellular hsp90a for their ability to limit metastasis in a new model developed by our collaborators at Tufts using human breast cancer cells metastasizing to human bone explants in immunocompromised mice (Aim 3). Thus, these experiments take us from an initial discovery of hsp90a function with cell-based assays to in vivo animal models taking an interdisciplinary approach to address a key issue of human health: limiting metastasis to improve breast cancer prognosis. These studies aim to expedite the translation of our basic research into a potential therapy. If successful, the proposed work would provide data for developing future clinical studies and thus impact human health.

描述（由申请人提供）：绝大多数乳腺癌相关死亡是由于转移后的继发性肿瘤造成的。目前没有有效的疗法来限制转移。我们的长期目标是开发减少癌症侵袭的新疗法，这是转移的关键第一步。该提议基于我们的观察，即通过激活基质金属蛋白酶 MMP2，癌症侵袭需要一种新型细胞外形式的分子伴侣 hsp90a。 Hsp90 与癌症有关，具有抗肿瘤活性的 hsp90 抑制剂目前正在进行临床试验。这些药物可能存在问题，因为它们干扰 hsp90 的许多细胞内功能。我们的研究结果表明我们的主要假设是抑制细胞外 hsp90a 将减少侵袭，从而限制转移。这为通过抑制侵袭而不干扰 hsp90 的无数细胞内功能来进行新型抗癌治疗提供了机会。为了支持这一想法，我们将实现三个具体目标。我们将确定 hsp90a 在癌细胞外部发挥作用的机制（目标 1）。然后，我们将利用这些信息来开发和测试细胞外 ​​hsp90 抑制剂（目标 2）。我们已经拥有一种非渗透性 hsp90 抑制剂，以及来自 NCI 和 Xerion Pharmaceuticals 合作者的几种中和单链抗体候选药物。最后，我们将在塔夫茨大学的合作者开发的新模型中测试这些最好的细胞外 hsp90a 抑制剂限制转移的能力，该模型使用在免疫功能低下的小鼠中转移到人骨外植体的人乳腺癌细胞（目标 3）。因此，这些实验使我们从基于细胞的检测初步发现 hsp90a 功能，到采用跨学科方法解决人类健康的关键问题的体内动物模型：限制转移以改善乳腺癌预后。这些研究旨在加快将我们的基础研究转化为潜在的疗法。如果成功，拟议的工作将为开发未来的临床研究提供数据，从而影响人类健康。