Inhibiting extracellular Hsp90 to reduce breast cancer metastasis

抑制细胞外Hsp90减少乳腺癌转移

• 批准号: 9036063
• 负责人: Daniel G. Jay
• 金额: $ 37.74万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-28 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036063
• 关键词: Accounting; Adverse effects; Affect; Animal Model; Biological Markers; Breast; Breast Cancer Patient; Breast cancer metastasis; Cancer Model; Cell physiology; Cells; Cessation of life; Client; Clinical; Clinical Trials; Collaborations; Communication; Data; Development; Diabetes Mellitus; Diagnostic; Disease; Drosophila pros protein; Drug Kinetics; Drug Targeting; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Gelatinase A; Goals; Human; Knowledge; LOXL2 gene; Lead; Malignant Bone Neoplasm; Malignant Neoplasms; Mediating; Metastatic breast cancer; MicroRNAs; Molecular Chaperones; Mus; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Pathogenesis; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Physiology; Process; Proteins; Publishing; Qualifying; Reagent; Research; Role; Sampling; Serum; Structure; Testing; Toxic effect; Work; Xenograft Model; authority; base; bone; bone xenograft; cancer biomarkers; cancer cell; cancer invasiveness; cancer survival; cancer therapy; cell motility; chemotherapy; combinatorial; cytotoxicity; exosome; extracellular; in vivo; inhibitor/antagonist; innovation; interest; lung Carcinoma; malignant breast neoplasm; migration; mortality; mouse model; novel; prevent; protein function; public health relevance; skills; trafficking; tumor; tumor progression; uptake

 DESCRIPTION (provided by applicant): Finding drugs that target breast cancer invasion (the first step in metastasis) without affecting normal tissue is an important unmet goal. One protein target of high current interest is the molecular chaperone Hsp90, which functions in cancer progression and metastasis as well as normal cell function. Hsp90 inhibitors such as ganetespib are currently in clinical trials, however they may have serious side effects based on the many proteins that require Hsp90 for activation. We introduced the concept of inhibiting Hsp90 outside of cancer cells to circumvent this problem. My lab first showed that extracellular Hsp90 (eHsp90) is released by cancer cells and that it acts in cancer invasion by activation of Matrix Metalloproteinase-2. Since then, we and others have shown that eHsp90 activates many pro-proteins in the extracellular media to enhance invasion including Lysyl Oxidase-like 2 (LOXL2), which remodels the extracellular matrix and is well implicated in cancer. We also showed that eHsp90 is released from cells via exosomes and, in new data, we show that inhibiting Hsp90 reduces exosome release and uptake, which has been implicated in tumor communication during invasion. Inhibiting eHsp90 may prevent this thus reducing invasion and metastasis. Our long-term goal is to achieve a clinical trial for an eHsp90 inhibitor for breast cancer. Recently we showed that STA-12-7191 (an impermeant derivative of ganetespib) inhibits cancer cell motility but is 5-fold less toxic to normal cells. These findings suggest that specifically inhibiting eHsp90 will benefit cancer treatment by preventing activation of LOXL2 and exosome release, reducing invasion without the damaging effects of inhibition of Hsp90's intracellular functions. We will test this hypothesis in the following Aims: 1. Test if LOXL2 is a bona fide eHsp90 client thereby providing a biomarker for eHsp90 inhibition in vivo; 2. Determine how eHsp90 acts in exosome trafficking and show this is pro-invasive; 3. Test the association between serum eHsp90 levels and metastatic breast cancer using clinically annotated patient sera and a novel ELISA diagnostic; and 4. Test the role of eHsp90 in breast cancer metastasis in human breast-to-bone xenograft model. We bring together an outstanding collaborative team including the PI who pioneered eHsp90, Dr. Ying who developed ganetespib and STA-12-7191 and experts in Hsp90 (Neckers), breast cancer biomarkers (Seewaldt and Luo) and metastasis animal models (Kuperwasser). This study is significant because it would validate eHsp90 as an important drug target for treating metastatic breast cancer and implicate it in two important pro-invasive processes: exosome-based tumor communication and ECM remodeling by LOXL2. Importantly, this study could lead to a drug that would inhibit these processes with fewer side effects than the Hsp90 inhibitors currently in human trials. In addition, it would impact other cancers and other diseases given eHsp90's multiple roles in pathogenesis. The work is innovative because it tests a novel mechanism for exosome trafficking and introduces a novel compound to inhibit eHsp90 and testing its benefit in cancer.

 描述(由申请人提供)：寻找针对乳腺癌侵袭(转移的第一步)而不影响正常组织的药物是一个重要的未实现的目标。目前感兴趣的一个蛋白质靶标是分子伴侣Hsp90，它在癌症的进展和转移以及正常细胞功能中发挥作用。HSP90抑制剂，如Ganetespib，目前正在进行临床试验，但它们可能会有严重的副作用，因为许多蛋白质需要Hsp90才能激活。我们引入了在癌细胞外抑制Hsp90的概念来绕过这个问题。我的实验室首先证明了细胞外Hsp90(EHsp90)是由癌细胞释放的，它通过激活基质金属蛋白酶-2在癌症侵袭中发挥作用。从那时起，我们和其他人已经证明，eHsp90激活细胞外介质中的许多前蛋白以增强侵袭，包括Lysyl Oxidase-like 2(LOXL2)，它重塑细胞外基质，与癌症密切相关。我们还表明eHsp90是通过外切体从细胞中释放出来的，在新的数据中，我们表明抑制Hsp90减少了外切体的释放和摄取，这与肿瘤侵袭过程中的通讯有关。抑制eHsp90可能会阻止这一过程，从而减少侵袭和转移。我们的长期目标是实现eHsp90乳腺癌抑制剂的临床试验。最近，我们发现了STA-12-7191(一种不必要的Ganetespib衍生物)可以抑制癌细胞的运动，但对正常细胞的毒性却降低了五分之一。这些发现表明， 特异性地抑制eHsp90将通过阻止LOXL2的激活和外切体的释放而有利于癌症的治疗，减少侵袭，而不会受到抑制Hsp90‘S细胞内功能的破坏性影响。我们将从以下几个方面测试这一假说：1.测试LOXL2是否是真正的eHsp90客户，从而为体内eHsp90的抑制提供一个生物标记物；2.确定eHsp90如何在外体运输中发挥作用，并证明这是亲侵袭的；3.使用临床注释的患者血清和一种新的ELISA诊断方法来测试血清eHsp90水平与转移性乳腺癌之间的关联；以及4.在人类乳房到骨移植模型中测试eHsp90在乳腺癌转移中的作用。我们汇聚了一支出色的协作团队，其中包括开创eHsp90的PI、开发Ganetespib和STA-12-7191的Ying博士，以及Hsp90(颈部)、乳腺癌生物标记物(Seewaldt和Luo)和转移动物模型(Kuperwasser)的专家。这项研究具有重要意义，因为它将验证eHsp90作为治疗转移性乳腺癌的重要药物靶点，并涉及两个重要的促侵袭过程：基于外切体的肿瘤通讯和LOXL2的ECM重塑。重要的是，这项研究可能会导致一种药物，它可以抑制这些过程，副作用比目前正在进行人体试验的Hsp90抑制剂更少。此外, 它将影响其他癌症和其他疾病，赋予eHsp90‘S在发病机制中的多重作用。这项工作具有创新性，因为它测试了一种新的外切体运输机制，并引入了一种新的化合物来抑制eHsp90，并测试了其在癌症中的益处。