Bench to Bedside: Therapeutic Approaches to Prevent Radiation Therapy- and Spaceflight-Induced Bone Toxicity

Jeff Willey, Ph.D.
Associate Professor of Radiation Oncology
Wake Forest School of Medicine
Thu, September 17, 2020 at 2:30 PM

Approximately half of all new cancer diagnoses will receive ionizing radiation.  As improvements in screening and treatment decrease patient mortality, radiation therapy (RT)-induced bone fracture (radiation-induced fracture; RIF) has become a major problem.  For instance, the risk of developing a pelvic fracture at 5 years post RT is ~30% in women treated for endometrial adenocarcinoma.  Outcomes are poor following RIF, and thus RIF is a persistent and major source of functional impairment, pain, and mortality in many cancer survivors.  Bone damage has historically been thought to result from a persistent low bone turnover state due to damaged osteoblasts.  However, our preclinical (in vitro and in vivo) models have identified an early increase in osteoclast activity after irradiation, causing an acute, active loss of bone volume and architecture.  This early increase in osteoclast activity serves as a potential therapeutic target if observed clinically; however, as noted, the bone loss thought to be responsible for RIF is considered a late-developing response.  Our collaborative team of physicians, engineers, physicists, and biologists developed an imaging platform capable of identifying rapid changes in bone density and architecture after RT.  This cortical thickness and radiation dose-mapping approach can be utilized as a means to monitor the rate of bone loss in our patients treated with several clinical RT protocols, including changes in bone from: i] the ribs after stereotactic body radiation therapy (SBRT) for primary or metastatic lung lesions; and ii] the hip and femoral neck after intensity modulated radiation therapy (IMRT) for anal cancer.   Applying this technique identified substantial early thinning of rib cortical bone at 3 month follow-up in the regions of ribs that absorb >10 Gy during SBRT, and was localized at sites of fractures within the first year.  Additionally, dose dependent thinning of the inferior-anterior and inferior-posterior portions of the femoral neck was observed in anal cancer patients by ~3 months.  This high rate of bone loss at irradiated sites strongly suggests increased osteoclast activity as a mediator of RT-induced bone toxicity, which can be targeted with appropriate therapeutics such as bisphosphonates, and are now the basis for an ongoing prospective clinical trial.

Jeff Willey, Ph.D.

Dr. Willey received his PhD in Bioengineering at Clemson University in 2008.  He completed a National Space Biomedical Research Institute (NSBRI) postdoctoral fellowship studying the cause, progression, and prevention of the radiation-induced bone loss from simulated spaceflight conditions (e.g., low dose radiation and/or microgravity).  His second postdoctoral fellowship in the Translational Radiation Oncology (TRADONC) T-32 program at Wake Forest School of Medicine focused on preventing skeletal toxicity in cancer survivors.  His current NIH- and NASA-funded research program continues to test therapies to prevent musculoskeletal toxicity from radiation therapy and during spaceflight.  Dr. Willey has performed both NASA-funded research and educational outreach throughout his career, serving as a PI for the Rodent Research-9 Science Mission to the International Space Station on a SpaceX CRS-12 launch examining the extent of arthritic responses in-flight, and a primary science team member for two space shuttle missions investigating bone and muscle loss prevention during time in orbit.  Since 2018, he has served as the Director of the Red Risk School sponsored by Translational Research Institute for Space Health through NASA.  His research laboratory is dedicated to both graduate and resident education and training aimed at improving the quality of life for cancer survivors and astronauts.