Inhibiting extracellular Hsp90 to reduce breast cancer metastasis

抑制细胞外Hsp90减少乳腺癌转移

• 批准号: 10304858
• 负责人: Daniel G. Jay
• 金额: $ 11.96万
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304858
• 关键词: Accounting; 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; Diagnostic Reagent Kits; Disease; Drosophila pros protein; Drug Kinetics; Drug Targeting; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Gelatinase A; Goals; HSP 90 inhibition; 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; 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; innovation; interest; lung Carcinoma; malignant breast neoplasm; migration; mortality; mouse model; novel; prevent; protein function; public health relevance; side effect; 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（由适用提供）：发现靶向乳腺癌侵袭的药物（转移的第一步）而不影响正常组织是一个重要的未得到的目标。高电兴趣的一个蛋白质靶标是分子链酮HSP90，它在癌症进展和转移以及正常细胞功能中起作用。 HSP90抑制剂（例如Casetespib）目前正在临床试验中，但是它们可能会基于许多需要HSP90激活的蛋白质具有严重的副作用。我们介绍了抑制癌细胞以外的HSP90以解决此问题的概念。我的实验室首先表明，细胞外HSP90（EHSP90）由癌细胞释放，并且通过激活基质金属蛋白酶2的激活来起作用。从那时起，我们和其他人表明，EHSP90在细胞外培养基中激活许多蛋白质，以增强侵袭，包括赖氨酸氧化酶样2（LOXL2），该酶氧化酶样2（LOXL2）重塑了细胞外基质，并在癌症中得到很好的实现。我们还表明，EHSP90通过外泌体从细胞中释放出来，在新数据中，我们表明抑制HSP90会降低外泌体释放和摄取，这在侵袭过程中已在肿瘤通信中浸渍。抑制EHSP90可能会阻止这种情况减少侵袭和转移。我们的长期目标是实现EHSP90乳腺癌抑制剂的临床试验。最近，我们表明STA-12-7191（Casetespib的渗透衍生物）抑制了癌细胞的运动性，但对正常细胞的毒性低5倍。这些发现表明 特别抑制EHSP90将通过防止LOXL2和外泌体释放的激活来使癌症治疗受益，从而减少浸润，而不会抑制HSP90的细胞内功能。我们将在以下目的中检验该假设：1。测试LOXL2是否是真正的EHSP90客户端，从而为EHSP90抑制体提供了生物标志物； 2。确定EHSP90在外泌体贩运中的作用，并表明这是侵袭性的； 3。使用临床注释的患者血清和新型ELISA诊断测试血清EHSP90水平与转移性乳腺癌之间的关联；和4。测试EHSP90在人乳腺骨外束模型中的乳腺癌转移中的作用。我们组建了一个杰出的合作团队，其中包括PI开创了EHSP90，Ying博士，他开发了Gastosepib和STA-12-2-7191，以及HSP90（Neckers）（Neckers），乳腺癌生物标志物（Seewaldt and Luo）和Metastasis动物模型（Kuperwasser）（Kuperwasser）的专家。这项研究很重要，因为它将验证EHSP90是治疗转移性乳腺癌的重要药物靶标，并将其牵涉到两个重要的促侵入性过程中：基于外部的肿瘤通信和通过LOXL2进行ECM重塑。重要的是，这项研究可能导致一种药物，该药物比目前在人类试验中的HSP90抑制剂抑制这些过程的副作用更少。此外， 考虑到EHSP90在发病机理中的多重作用，它将影响其他癌症和其他疾病。这项工作具有创新性，因为它测试了外部贩运的新型机制，并引入了一种新颖的化合物来抑制EHSP90并测试其在癌症中的益处。