Margarete Akens

Research Synopsis

Effects of Non-Ionizing and Ionizing Radiation on Bone

Ionization radiation on bone: Prevention of radiation exposure to healthy bone has been a priority in radiotherapy. Despite this, however, and with the advent of intensity modulated radiotherapy treatments, the incidence of the late effects of radiation treatment including the impact on bone is still a major concern. Collateral damage from radiation treatment for oropharyngeal cancers and other head and neck malignancies can lead to the development of jaw osteoradionecrosis (ORN). The etiology of ORN is not completely understood yet, however, changes in blood supply have been observed and local ischemia is thought to be the main cause for the bone tissue to die. Pre-clinical studies have neglected the impact that both systemic and local immune factors may play in the role of maintaining skeletal health and these models investigating the effect of radiation on bone are predominately performed on healthy animals. The presence of a tumor modulates the immune system, which likely results in a different response of the bone to the radiotherapy compared to healthy bone. It has been shown, that the immune system plays an important role in bone remodeling and skeletal homeostasis and clearly this will impact on the incidence of osteoradionecrosis. Therefore, I started establishing a clinical relevant, tumor bearing animal model of osteoradionecrosis by injecting VX-2 tumour cells into the masseter muscle close to the mandible, which is included in the radiation treatment of the tumour.  - Other areas of the skeleton are affected by radiation when soft tissue sarcomas treated either before or after surgery. Secondary pathological fractures continue to be a major concern particularly when these tumors are closely located to the bone, specifically the femur. Pathological fractures continue to represent a significant challenge and are difficult to treat with poor healing potential. I will utilize the VX-2 tumour model and treat the tumour injected into the quadriceps muscle close to the femur with radiation and follow the changes to the bone with different imaging modalities followed by histology. These animal models will allow studying site-specific pathophysiological mechanisms of radiotherapy to the skeletal system and will serve in the evaluation of new treatments.

Non-ionization radiation on bone: Studying the effect of photodynamic therapy (PDT) on vertebral metastases has shown that PDT, in addition to killing tumour, rapidly improved vertebral bone strength, stiffness and architecture. This exciting finding led me begin investigating the potential effect of PDT on fracture healing. In this preliminary work, I have investigated the potential of PDT and its time course of application to enhance fracture healing in commuted tibia fractures and critical sized femoral defects in the rat. Preliminary results treating commuted tibia fractures have shown an increase in bone formation and local VEGF expression and a concurrent decrease in serum VEGF level after PDT treatment, with best results at 7 days post injury. Preliminary results in the critical size femoral defect model have shown a decrease in gap size and more bone formation in the PDT treated groups only when the fracture gap at surgery was ≥6 mm. Further studies with longer time-points and a defect ≥6 mm are necessary to validate these observations.

Comparative Oncology Program: Additionally I’m leading the emerging Comparative Oncology Program at STTARR. Cancer occurs naturally in animals with a similar frequency as in humans, but due to the shorter life span everything happens faster. This program focusses on collaboration between Veterinarians and Physicians to accelerate the knowledge about cancer biology and clinical care.

Recent Publications

• Oakden W, Kwiecien JM, O'Reilly MA, Lake EM, Akens MK, Aubert I, et al. A non-surgical model of cervical spinal cord injury induced with focused ultrasound and microbubbles. Journal of neuroscience methods. 2014;235C:92-100.
• Akens MK, Wise-Milestone L, Won E, Schwock J, Yee AJM, Wilson BC, et al. In-vitro and in-vivo effects of photodynamic therapy on metastatic breast cancer cells pre-treated with zoledronic acid Photodiagn Photodyn Ther. 2014.
• Pezeshki PS, Woo J, Akens MK, Davies JE, Gofeld M, Whyne CM, et al. Evaluation of a bipolar-cooled radiofrequency device for ablation of bone metastases: preclinical assessment in porcine vertebrae. Spine J. 2014;14(2):361-70.
• Lo VC, Akens MK, Moore S, Yee AJ, Wilson BC, Whyne CM. Beyond radiation therapy: photodynamic therapy maintains structural integrity of irradiated healthy and metastatically involved vertebrae in a pre-clinical in vivo model. Breast Cancer Res Treat. 2012;135(2):391-401.
• Liu TW, Akens MK, Chen J, Wise-Milestone L, Wilson BC, Zheng G. Imaging of specific activation of photodynamic molecular beacons in breast cancer vertebral metastases. Bioconjug Chem. 2011;22(6):1021-30.
• Tuer AE, Akens MK, Krouglov S, Sandkuijl D, Wilson BC, Whyne CM, et al. Hierarchical model of fibrillar collagen organization for interpreting the second-order susceptibility tensors in biological tissue. Biophysical journal. 2012;103(10):2093-105.
• Wise-Milestone L, Akens MK, Lo VC, Yee AJ, Wilson BC, Whyne CM. Local treatment of mixed osteolytic/osteoblastic spinal metastases: is photodynamic therapy effective? Breast Cancer Res Treat. 2012;133(3):899-908.