Novel Dual-Modality Treatment of Breast Cancer-Induced Osteolysis

乳腺癌引起的骨溶解的新型双模式治疗

• 批准号: 10724723
• 负责人: DAWN M ELLIOTT
• 金额: $ 30.68万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724723
• 关键词: 4T1; Acceleration; Address; Age Months; Aging; Animal Model; Binding; Biological Markers; Biomechanics; Body Weight; Bone Growth; Bone Marrow; Bone structure; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast cancer metastasis; Cancer Patient; Cell membrane; Cells; Centers of Research Excellence; Combined Modality Therapy; Data; Doxorubicin; Estrogen deficiency; Exercise; Exhibits; Fatigue; Flow Cytometry; Fracture; Frequencies; Fright; Funding; Gene Expression Profiling; Grant; Health; Health Benefit; Histology; Immunohistochemistry; Inbred BALB C Mice; Induction of Apoptosis; Injections; Ion Channel; Literature; Luciferases; Marrow; Measures; Membrane; Metastasis Induction; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Modality; Mus; Musculoskeletal; Musculoskeletal System; Neoplasm Metastasis; Osteocytes; Osteogenesis; Osteolysis; Outcome; Ovariectomy; Pain; Parents; Patients; Pharmaceutical Preparations; Piezo 1 ion channel; Postmenopause; Primary Neoplasm; Proteins; Recurrent Malignant Neoplasm; Research; Resources; Serum; Site; Surface; Testing; Therapeutic exercise; Tissues; Toxic effect; Tumor Burden; United States National Institutes of Health; Validation; Woman; Women' s Health; aged; anticancer treatment; bioluminescence imaging; bone; bone cell; bone health; bone imaging; bone loss; cancer cell; cancer imaging; cancer recurrence; cancer therapy; carcinogenesis; chemotherapy; combat; high risk; improved; in vivo; intravenous injection; malignant breast neoplasm; mechanical signal; mechanotransduction; microCT; multimodality; nanomedicine; nanoparticle; nanopolymer; novel; primary outcome; protective effect; response; skeletal; targeted delivery; targeted treatment; treatment effect; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression; vibration

Project Summary Bone is one of the top sites for breast cancer metastasis, and cancer-induced bone loss puts patients at high risk of painful or even fatal fractures. Exercise with proven benefits of promoting bone and reducing cancer recurrence is commonly prescribed. However, exercise is challenging for many cancer patients due to treatment- induced fatigue and fear of activity-related fractures. Moreover, postmenopausal breast cancer patients exhibit reduced response to exercise due to aging, estrogen deficiency, and chemotherapy-induced apoptosis of osteocytes, the primary mechanosensing cells in bone. Thus, targeted delivery of chemotherapy to primary and metastatic tumors while increasing bone’s response to exercise is both desirable and necessary to treat breast cancer bone metastasis. Whole body vibration is an exercise alternative that generates high-frequency low- magnitude mechanical signals that stimulate the musculoskeletal system. Pilot data from Dr. Liyun Wang (Project Co-Lead) demonstrated that whole body vibration augmented with Yoda1, a highly selective activator of Piezo1 ion channels, promoted significant periosteal bone formation in aged mice with and without triple-negative breast cancer (TNBC) tumors, leading to enhanced skeletal integrity and delayed bone destruction by tumors. Due to the invasiveness of the tumors, the skeletal protective effects diminished as tumor growth accelerated. To combat tumor progression, Dr. Emily Day (Project Co-Lead) has developed drug-loaded polymer nanoparticles (NPs) that are wrapped with plasma membranes derived from TNBC cells. These membrane-wrapped nanoparticles (MWNPs) were shown to selectively bind to and kill TNBC cells in vivo due to the unique proteins expressed on the cancer cell membrane surfaces. Together, we propose to test a novel combination therapy that targets bone’s mechanosensitivity via Piezo1 activation and suppresses tumor growth via MWNPs carrying the chemotherapy drug doxorubicin (DOX). Our hypothesis is that Yoda1-augmented whole-body vibration could promote periosteal bone formation in ovariectomized mice bearing metastatic breast cancers, while DOX-loaded MWNPs would simultaneously suppress metastatic tumors in bone marrow and minimize off-target bone damage, resulting in health benefits with reduced tumor burden and increased skeletal integrity. In this one-year supplement, we will investigate the treatment effects of DOX-loaded MWNPs and Yoda1-augmented whole-body vibration, alone or combined, on tumor growth (Aim 1) as well as on the integrity of bone (Aim 2). Successful completion of the project will prove the concept of developing safe therapeutic exercise alternatives combined with anti-cancer treatment with high selectivity and reduced off-target toxicity for metastatic breast cancer patients. This application addresses a significant health threat to women (breast cancer induced fractures), aligns with the overall musculoskeletal focus of the parent COBRE grant, and will lead to submission of a NIH R01 or DoD proposal for in-depth studies of the novel multimodal cancer treatment.

项目摘要 骨是乳腺癌转移的主要部位之一，癌症引起的骨丢失使患者处于高风险状态。 疼痛甚至致命骨折的风险。运动与促进骨骼和减少癌症的证明好处 通常规定复发。然而，由于治疗，运动对许多癌症患者来说是具有挑战性的- 诱发疲劳和对活动相关骨折的恐惧。此外，绝经后乳腺癌患者表现出 由于衰老、雌激素缺乏和化疗诱导的细胞凋亡， 骨细胞是骨骼中的主要机械感受细胞。因此，将化疗靶向递送至原发性和非原发性肿瘤， 转移性肿瘤，同时增加骨骼对运动的反应是治疗乳腺癌的理想和必要的。 癌症骨转移全身振动是一种运动的替代品，产生高频率的低- 刺激肌肉骨骼系统的机械信号。Liyun Wang博士的试验数据（项目 Co-Lead）证明，全身振动与Yoda 1（一种高度选择性的Piezo 1激活剂）一起增强 离子通道，促进有和没有三阴性乳腺癌的老年小鼠显著的骨膜骨形成 这导致增强的骨骼完整性和延迟的肿瘤引起的骨破坏。由于 肿瘤的侵袭性，骨骼保护作用随着肿瘤生长的加速而减弱。到 为了对抗肿瘤进展，艾米丽戴博士（项目共同负责人）开发了载药聚合物纳米颗粒 (NPs)其被来自TNBC细胞的质膜包裹。这些薄膜包裹的 由于独特的蛋白质，纳米颗粒（MWNPs）显示出在体内选择性地结合并杀死TNBC细胞 在癌细胞膜表面表达。我们一起提出测试一种新的联合疗法 通过Piezo 1激活靶向骨的机械敏感性，并通过携带MWNPs抑制肿瘤生长， 化疗药物阿霉素（DOX）。我们的假设是，尤达1增强的全身振动可以 促进转移性乳腺癌卵巢切除小鼠骨膜骨形成，而DOX负载 MWNPs将同时抑制骨髓中的转移性肿瘤并使脱靶骨最小化。 损伤，导致健康益处，减少肿瘤负担和增加骨骼完整性。在这一年里， 作为补充，我们将研究DOX负载的MWNPs和Yoda 1增强的全身治疗效果。 振动，单独或组合，对肿瘤生长（目标1）以及对骨的完整性（目标2）。成功 该项目的完成将证明开发安全的治疗性运动替代品的概念， 对于转移性乳腺癌具有高选择性和降低的脱靶毒性的抗癌治疗 患者该应用程序解决了对女性的重大健康威胁（乳腺癌引起的骨折）， 与母公司COBRE资助的整体肌肉骨骼重点，并将导致提交NIH R 01或 美国国防部提议对新型多模式癌症治疗进行深入研究。