INHIBITING SURFACE HSP90 TO LIMIT METASTASIS

抑制表面 HSP90 以限制转移

• 批准号: 6964418
• 负责人: Daniel G. Jay
• 金额: $ 29.06万
• 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/6964418
• 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）：绝大多数与乳腺癌相关的死亡是由于转移后的继发性肿瘤。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。该建议是基于我们的观察结果，即通过激活基质金属蛋白酶MMP2，需要一种新型的细胞外伴侣HSP90A来癌症侵袭。 HSP90与癌症有关，HSP90具有抗肿瘤活性的抑制剂目前正在临床试验中。这些药物可能是有问题的，因为它们干扰了HSP90的许多细胞内功能。我们的发现表明，我们的主要假设是抑制细胞外Hsp90a将降低浸润，从而限制转移。这为新型抗癌治疗提供了一个机会，可以抑制入侵而不干扰HSP90的无数细胞内功能。为了支持这个想法，我们将解决三个具体目标。我们将确定HSP90A在癌细胞外部的功能的机制（AIM 1）。然后，我们将使用此信息来开发和测试细胞外HSP90抑制剂（AIM 2）。我们已经手头上有一个无形的HSP90抑制剂，还有一些候选者可以中和我们在NCI和Xerion Pharmaceuticals的合作者中和单链抗体。最后，我们将测试这些细胞外HSP90A的抑制剂中最好的抑制剂，以便在我们的合作者使用人类乳腺癌细胞转移到免疫功能低下的小鼠中的人乳腺癌细胞向人类骨外植体转移到塔夫茨的新模型中限制转移的能力（AIM 3）。因此，这些实验使我们从最初发现的HSP90A功能和基于细胞的测定方法的情况下，以跨学科的方法来解决人类健康的关键问题：限制转移以改善乳腺癌的预后。这些研究旨在加快将我们的基础研究转化为潜在疗法。如果成功，建议的工作将为发展未来的临床研究提供数据，从而影响人类健康。