William Thompson, DPT, Ph.D.
1140 W. Michigan Street
Indianapolis, IN 46202
Phone: (317) 278-9619
Research Program Membership
Dr. Thompson's research interests include:
Current work, that is funded by a recently awarded DoD grant, investigates the capacity of very low magnitude mechanical signals, alone or in combination with bisphosphonates, to suppress bone and muscle loss resulting from aromatase inhibitor induced estrogen depletion and to restrict breast cancer bone metastases. Aromatase inhibitors (AIs) drastically deplete peripheral 17β-estradiol (E2) concentrations and are a standard adjuvant treatment for estrogen receptor-positive (ER+) breast cancer. Unlike selective estrogen receptor modulators (SERMs), which spare bone, AIs lead to severe bone loss and musculoskeletal complications resulting in low compliance. The mechanism of AI-induced muscular dysfunction has not been identified; however, increased osteoclastic bone resorption, resulting from AI-induced E2 depletion, could alter the bone microenvironment by releasing matrix-derived growth factors that prime the pre-metastatic niche, increase breast cancer progression in bone, and exacerbate muscle weakness. Thus, there is need for safe treatment to offset these deleterious effects. Low-magnitude mechanical signals, delivered at a high frequency, activate anabolic intracellular signaling pathways, and when dosed correctly, serve as a surrogate exercise intervention. These safe, clinically effective mechanical signals are delivered using low-intensity vibration (LIV) platforms and have been shown to enhance bone formation and muscle strength in animals and humans. In mouse models of ovarian cancer and myeloma, LIV prevented bone loss; and restricted myeloma tumor progression. The effect of LIV to protect the musculoskeletal system from the negative effects of E2 deprivation therapy or bone metastases has not been explored. Current studies are evaluating the effects and novel mechanisms of LIV on AI-induced musculoskeletal complications and to prevent breast cancer bone metastases. Hypothesis: Low-magnitude mechanical signals, alone or in combination with a bisphosphonate, suppress bone and muscle loss resulting from aromatase inhibitor (AI)-induced estrogen (E2) depletion and restricts breast cancer bone metastases. AIM 1: In vivo, demonstrate that LIV therapy prevents the progression of breast cancer bone metastases in estrogen-deprived mice. Design: A) Ovariectomized (OVX) and AI (letrozole) treated mice given LIV alone, bisphosphonate (zoledronic acid, ZA) alone, or LIV/ZA in combination and will be assessed for changes in bone density and strength as well as muscle size and contractility. B) Ability of LIV and/or ZA to reduce the progression of bone metastases following intra-cardiac inoculation of MDA-MB-231 human breast cancer cells will be assessed by measuring tumor burden in bone and soft tissues, and by examining osteolytic lesions. C) We will examine biochemical modifications that destabilize key calcium channels (RyR1 and SERCA1) relative to sham (no vibration), vehicle-treated mice. AIM 2: In vivo, demonstrate that LIV therapy has direct effects on bone and skeletal muscle tissue in non-tumor bearing, estrogen deficient mice. Design: A) Non tumor-bearing mice will be pretreated with LIV and/or bisphosphonate, followed by E2 deprivation therapy. Mice will be followed for changes in bone and muscle function. B) Biochemical modifications to calcium channels (RyR1, SERCA1) and functional changes in calcium handling in skeletal muscle in non cancer-bearing mice will be assessed following LIV and/or bisphosphonate treatment. C) The quantity of marrow stem cell population and expression of nuclear envelope proteins following LIV and/or ZA treatment will be determined. AIM 3: Determine the role of the structural connections between the nucleus and cytoskeleton on the anti-tumor and protective effects of LIV on musculoskeletal tissues in vivo and in vitro. Impact: At least a third of breast cancer patients prematurely discontinue life-prolonging adjuvant AI treatment due to unmanageable AI-induced musculoskeletal complications. Thus, there is great need for interventions to improve musculoskeletal outcomes in these patients, as proposed here. Demonstration of efficacy in our animal models would provide proof-of-concept for clinical testing of LIV in breast cancer patients. Future studies, which are proposed in an upcoming R01 submission with Dr. Theresa Guise, will investigate the ability of LIV to suppress muscle and bone loss associated with androgen deficiency and prostate cancer metastases.
Post-doctoral Fellowship - University of North Carolina, Chapel Hill, NC 2014
Post-doctoral Fellowship - University of Delaware, Newark, DE 2011
Ph.D. - University of Delaware, Newark, DE 2010
D.P.T. - University of Delaware, Newark, DE 2007