Monday, October 2, 2023
10/2/2023
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.
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