PREVENT PRECLINICAL EFFICACY AND INTERMEDIATE BIOMARKER ENDPOINTS TASK ORDER: USE OF CARNOSIC ACID AND VIVOX40 FOR BREAST CANCER PREVENTION

预防临床前功效和中间生物标志物终点任务顺序：使用鼠尾草酸和 VIVOX40 预防乳腺癌

• 批准号: 10269185
• 负责人: ALEX LYUBIMOV
• 金额: $ 107.16万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-02-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269185
• 关键词: Aromatase Inhibitors; Attenuated; BCL9 gene; Basement membrane; Binding; Biological Markers; Breast; Breast Cancer Prevention; Cell Line; Cell Proliferation; Cells; Characteristics; Chemopreventive Agent; Detection; Development; Disease; Dose; Duct (organ) structure; Endometrial Carcinoma; Epithelial; Epithelium; European; Evolution; Excision; Food Additives; Food Safety; Genetic Transcription; Genetically Engineered Mouse; Goals; Hela Cells; Heterogeneity; Hot flushes; Human; In Situ Lesion; Individual; Indolent; Mammary Neoplasms; Mesenchymal; Modeling; Molecular; Mus; Myoepithelial cell; Neoplasms; Night Sweating; Noninfiltrating Intraductal Carcinoma; Nuclear; Observational Study; Operative Surgical Procedures; Pathologic; Patients; Phase; Prevention therapy; Preventive; Radiation therapy; Recurrence; Regimen; Risk; Rosemary; SW480; Stroke; Tamoxifen; Time; Transgenic Mice; United States; United States Food and Drug Administration; anti-cancer; authority; beta catenin; bone loss; breast cancer progression; breast imaging; cancer cell; cancer type; dietary supplements; effective therapy; efficacy study; high risk; hormone receptor-negative; hormone receptor-positive; hormone therapy; improved; in vivo; in vivo Model; malignant breast neoplasm; mouse model; non-compliance; pharmacokinetics and pharmacodynamics; preclinical efficacy; predictive marker; prevent; salvin; side effect; small molecule inhibitor; thrombogenesis; tool; transplant model; tumor; tumor heterogeneity

Ductal Carcinoma In-Situ (DCIS) of the breast is the most common form of non-invasive breast cancer, with a marked increase in detection rate with improved breast imaging in the last few decades. About 16-30% of DCIS develop a recurrence in 10 years if treated with wide excision alone. DCIS is currently managed by surgical resection combined with radiotherapy. Following resection, the risk of recurrence is reduced by about one-half with breast radiotherapy and by an additional one-third with added anti-hormonal therapy such as tamoxifen or aromatase inhibitors, a benefit that is exclusive to individuals with hormone receptor positive DCIS. Anti-hormonal therapies, while effective, are associated with many side effects including hot flashes, night sweats, thrombogenesis, bone loss, stroke, and endometrial cancers. Consequently, the rate of non-compliance is as high as 50%. In contrast to hormone receptor positive DCIS, there are currently no preventive options for hormone receptor negative breast cancers. At the same time, evidence from observational studies suggests that a large fraction of DCIS, ~50%, are indolent and may not require surgical resection or radiotherapy. Therefore, there is an unmet need for the development of safer and more effective therapies for the prevention of human invasive breast cancer, for which ductal carcinoma in situ (DCIS) is a precursor. Non-clinical models of non-invasive breast tumors are limited, and the existing in vivo models do not mimic inter- and intratumoral heterogeneity. With the prevailing notion that human DCIS initiates inside the ducts, Behbod et al. developed the mouse intraductal (MIND) model to show whether subtypes of human DCIS might contain distinct subpopulations of tumor-initiating cells. The intraductal MIND transplantation model provides an invaluable tool that mimics human breast heterogeneity at the noninvasive stages and allows the study of the distinct molecular and cellular mechanisms of breast cancer progression. Similar to the evolution of human DCIS, DCIS cells injected intraductally into mice form in situ lesions followed by invasion into the surrounding stroma as cancer cells infiltrate the natural barriers of the myoepithelial cell layer and basement membrane. The MIND model mimics the progression of breast neoplasia from non-invasive (ductal carcinoma in situ) to invasive disease. This step is widely recognized as a critical transition, in that most invasive breast cancers are thought to evolve though a DCIS phase. Previous studies showed a significant association between high nuclear BCL9 and pathological characteristics indicative of high-risk DCIS. The in vivo silencing of BCL9 in DCIS MIND models, led to inhibition of DCIS invasion, reversal of epithelial mesenchymal transition (EMT), and a significant reduction in DCIS cellular proliferation. Additionally, de la Roche and colleagues performed a screen for small-molecule inhibitors of β-catenin binding to BCL9 and discovered carnosic acid, a natural compound found in rosemary extract (RE). Their studies showed that carnosic acid was non-toxic, induced proteosomal degradation of active β-catenin and attenuated BCL9/β-catenin-dependent transcription in HeLa and SW480 cells. In humans, RE has already been approved as a safe food additive by the United States Food and Drug Administration (USFDA) and by the European Food Safety Authority. Further, RE has been categorized by the FDA as “generally recognized as safe” or GRAS and Rosemary is widely available as dietary supplement in the United states. Numerous in vivo studies have provided strong evidence for the anti-cancer effects of rosemary extract and its principal component carnosic acid in various cancer types. The overall goal of the project is to evaluate chemopreventive effects of rosemary extract VivOX40 and carnosic acid in DCIS cell lines MIND graft, patient derived (PDX) DCIS MIND graft models and genetically engineered mouse models that recapitulate human breast cancer progression.

乳腺导管原位癌 (DCIS) 是最常见的非浸润性乳腺癌，在过去几十年中，随着乳腺影像学的改进，检出率显着增加，约 16-30% 的 DCIS 会复发。如果仅采用广泛切除治疗，DCIS 目前通过手术切除联合放疗进行治疗，切除后，乳房放疗可将复发风险降低约一半，而联合放疗可将复发风险降低三分之一。抗激素疗法，如他莫昔芬或芳香酶抑制剂，这是激素受体阳性 DCIS 患者独有的益处。 抗激素疗法虽然有效，但与许多副作用相关，包括潮热、盗汗、血栓形成、骨质流失、与激素受体阳性 DCIS 相比，目前尚无针对激素受体阴性乳腺癌的预防选择。同时，观察性研究的证据表明，很大一部分 DCIS（约 50%）是惰性的，可能不需要手术切除或放射治疗，因此，开发更安全、更有效的疗法来预防 DCIS 的需求尚未得到满足。人类浸润性乳腺癌，其中导管原位癌（DCIS）是非浸润性乳腺肿瘤的非临床模型是有限的，并且现有的体内模型不能模拟肿瘤间和肿瘤的异质性。盛行的鉴于人类导管原位癌 (DCIS) 起源于导管内的观点，Behbod 等人开发了小鼠导管内 (MIND) 模型，以显示人类导管原位癌 (DCIS) 的亚型是否可能包含不同的肿瘤起始细胞亚群。导管内 MIND 移植模型提供了一种模仿人类的宝贵工具。与人类 DCIS 的进化类似，DCIS 细胞被导管内注射到小鼠体内。随着癌细胞浸润肌上皮细胞层和基底膜的天然屏障，形成原位病变，随后侵入周围基质。MIND 模型模拟了乳腺肿瘤从非侵袭性（原位导管癌）到侵袭性疾病的进展。这一步骤被广泛认为是一个关键的转变，因为大多数浸润性乳腺癌被认为是通过 DCIS 阶段发展的。 先前的研究表明，高核 BCL9 与指示高风险 DCIS 的病理特征之间存在显着关联。此外，de la Roche 及其同事筛选了与 BCL9 结合的 β-连环蛋白小分子抑制剂，并发现了鼠尾草酸（一种天然化合物）。他们的研究表明，鼠尾草酸无毒，可诱导活性 β-连环蛋白的蛋白体降解，并减弱 HeLa 和 SW480 细胞中 BCL9/β-连环蛋白依赖性转录。经美国食品和药物管理局 (USFDA) 和欧洲食品安全局批准为安全食品添加剂。此外，RE 已被 FDA 归类为“普遍认为安全”或 GRAS，并且迷迭香在美国广泛用作膳食补充剂，大量体内研究为迷迭香提取物及其主要成分鼠尾草酸在各种癌症中的抗癌作用提供了有力的证据。迷迭香提取物 VivOX40 和鼠尾草酸对 DCIS 细胞系 MIND 移植物、患者来源 (PDX) DCIS MIND 移植模型和重现人类乳腺癌进展的基因工程小鼠模型的影响。