INHIBITING SURFACE HSP90 TO LIMIT METASTASIS

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。目前没有有效的治疗方法来限制转移。我们的长期目标是开发新的治疗方法，减少癌症侵袭，这是转移的关键第一步。这个建议是基于我们的观察，一种新的细胞外形式的分子伴侣热休克蛋白90 a是所需的活化的基质金属蛋白酶MMP 2的癌症侵袭。热休克蛋白90与癌症有关，具有抗肿瘤活性的热休克蛋白90抑制剂目前正在临床试验中。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，抑制细胞外热休克蛋白90 a将减少侵袭，从而限制转移。这为通过抑制侵袭而不干扰hsp90的无数细胞内功能的新型抗癌疗法提供了机会。为了支持这一想法，我们将讨论三个具体目标。我们将确定hsp90a如何在癌细胞外发挥作用的机制（目的1）。然后，我们将使用这些信息来开发和测试细胞外hsp90抑制剂（目标2）。我们已经有了一种不渗透的hsp90抑制剂，以及来自NCI和Xerion Pharmaceuticals的合作者的几种中和单链抗体的候选药物。最后，我们将测试这些细胞外hsp90a抑制剂中最好的抑制剂限制转移的能力，该新模型由我们在塔夫茨大学的合作者开发，使用转移到免疫功能低下小鼠人骨外植体的人乳腺癌细胞（Aim 3）。因此，这些实验使我们从最初发现的hsp90a功能与基于细胞的测定体内动物模型采取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，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。

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.