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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要骨骼是乳腺癌转移的主要部位之一，癌症引起的骨质流失使患者处于高水平运动已被证实对促进骨骼生长和减少癌症有好处。然而，由于治疗的原因，运动对于许多癌症患者来说是一项挑战。此外，绝经后乳腺癌患者表现出疲劳和对活动相关骨折的恐惧。由于衰老、雌激素缺乏和化疗诱导的细胞凋亡而对运动的反应降低骨细胞是骨骼中的主要机械传感细胞，因此，将化疗靶向递送至原发和中枢。转移性肿瘤同时增加骨骼对运动的反应对于治疗乳腺癌来说既是可取的也是必要的全身振动是一种产生高频低频的运动替代方案。刺激肌肉骨骼系统的机械信号来自 Liyun Wang 博士（项目）共同负责人）证明，Yoda1（一种 Piezo1 的高选择性激活剂）可增强全身振动离子通道，显着促进有或没有三阴性乳腺的老年小鼠的骨膜骨形成癌症（TNBC）肿瘤，导致骨骼完整性增强并延迟肿瘤引起的骨质破坏。随着肿瘤的侵袭性增加，骨骼的保护作用随着肿瘤生长的加速而减弱。 Emily Day 博士（项目联合负责人）开发了载药聚合物纳米粒子，以对抗肿瘤进展 (NP) 包裹着来自 TNBC 细胞的质膜。由于其独特的蛋白质，纳米颗粒（MWNP）被证明可以在体内选择性地结合并杀死 TNBC 细胞我们建议一起测试一种新的联合疗法。通过 Piezo1 激活来靶向骨骼的机械敏感性，并通过携带的 MWNP 抑制肿瘤生长我们的假设是，Yoda1 增强的全身振动可以治疗化疗药物阿霉素 (DOX)。促进患有转移性乳腺癌的卵巢切除小鼠的骨膜骨形成，而 DOX 负载 MWNPs 将同时抑制骨髓中的转移性肿瘤并最大限度地减少脱靶骨在这一年里补充，我们将研究负载 DOX 的 MWNP 和 Yoda1 增强全身的治疗效果单独或组合振动对肿瘤生长（目标 1）以及骨骼完整性（目标 2）的影响。该项目的完成将证明开发安全的治疗性运动替代方案的概念对转移性乳腺癌具有高选择性和降低脱靶毒性的抗癌治疗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），对齐。与母公司 COBRE 资助的整体肌肉骨骼重点一致，并将导致提交 NIH R01 或国防部提议深入研究新型多模式癌症治疗。