INHIBITING SURFACE HSP90 TO LIMIT METASTASIS

描述(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。目前还没有有效的治疗方法来限制转移。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。这一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，癌症侵袭需要一种新的细胞外形式的分子伴侣hsp90a。HSP90已被认为与癌症有关，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将减少侵袭，从而限制转移。这为新的抗癌治疗提供了机会，通过抑制侵袭而不干扰HSP90的无数细胞内功能。为了支持这一想法，我们将解决三个具体目标。我们将确定hsp90a在癌细胞外部的作用机制(目标1)。然后，我们将利用这些信息开发和测试细胞外HSP90抑制剂(目标2)。我们已经有了一种无效的HSP90抑制剂，以及来自我们在NCI和Xarion制药公司的合作者的几个候选中和单链抗体。最后，我们将在Tuft的合作者开发的一个新模型中测试这些细胞外hsp90a抑制剂中最好的它们限制转移的能力，该模型使用免疫受损小鼠中转移到人骨移植的人乳腺癌细胞(Aim 3)。因此，这些实验使我们从最初通过基于细胞的分析发现hsp90a的功能，到体内的动物模型，采用跨学科的方法来解决人类健康的一个关键问题：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治疗方法。如果成功，这项拟议的工作将为未来的临床研究提供数据，从而影响人类健康。

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.