Novel Dual-Modality Treatment of Breast Cancer-Induced Osteolysis

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度兴奋状态。 有疼痛甚至致命骨折的风险。已被证实具有促进骨骼和降低癌症益处的运动 复发是常见的处方药。然而，由于接受治疗，锻炼对许多癌症患者来说是具有挑战性的- 导致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导致的运动反应降低 骨细胞是骨骼中主要的机械传感细胞。因此，有针对性地向初级和中老年患者提供化疗 转移性肿瘤在增加骨骼对运动的反应的同时是治疗乳房的理想和必要的 癌症骨转移。全身振动是一种产生高频低频振动的运动替代方案。 刺激肌肉骨骼系统的大小机械信号。来自王丽云博士的试点数据(项目 共同铅)表明，Yoda1，一种高度选择性的Piezo1激活剂，增强了全身的振动 离子通道促进具有和不具有三重阴性乳房的老年小鼠显著的骨膜成骨 癌症(TNBC)肿瘤，导致骨骼完整性增强和肿瘤延迟的骨破坏。由于 肿瘤的侵袭性、骨骼保护作用随着肿瘤生长速度的加快而减弱。至 为了对抗肿瘤的进展，艾米丽·戴博士(项目联合负责人)开发出了载药聚合物纳米颗粒 (NPS)被来自TNBC细胞的质膜包裹。这些薄膜包裹着 纳米粒(MWNPs)由于其独特的蛋白质，在体内可以选择性地与TNBC细胞结合并杀伤细胞 在癌细胞膜表面表达。我们建议共同测试一种新的联合疗法 通过激活Piezo1靶向骨骼的机械敏感性，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，Yoda1增强的全身振动可以 卵巢切除荷转移性乳腺癌小鼠的骨膜成骨作用 MWNPs将同时抑制骨髓中的转移肿瘤，并最大限度地减少非靶向骨骼 损害，从而在减少肿瘤负担和增加骨骼完整性的同时对健康有益。在这一年里 作为补充，我们将研究负载DOX的MWNPs和Yoda1增强的全身治疗效果 单独或联合振动对肿瘤生长(目标1)以及对骨骼完整性(目标2)的影响。成功 该项目的完成将证明开发安全的综合治疗运动替代方案的概念 转移性乳腺癌高选择性、低非靶向毒性的抗癌治疗 病人。这项应用解决了对女性的重大健康威胁(乳腺癌导致的骨折)， 与母公司科布雷基金的整体肌肉骨骼重点，并将导致提交NIH R01或 国防部关于深入研究新型多模式癌症治疗的建议。

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.