Investigating novel therapies for osteosarcoma using advanced medical imaging

© 2012 Dr. Matthew L. BroadheadPublications included in thesis:Dowsey, M. M., Broadhead, M. L., Stoney, J. D. & Choong, P. F. (2009). Outcomes of total knee arthroplasty in English-versus non-English-speaking patients. Journal of Orthopaedic Surgery, 17(3), 305–309.Broadhead, M. L., Dass, C. R. & Choong, P. F. M. (2011). Systemically administered PEDF against primary and secondary tumours in a clinically relevant osteosarcoma model. British Journal of Cancer, 105(10), 1503–1511. DOI: 10.1038/bjc.2011.410Broadhead, M. L., Choong, P. F. M. & Dass, C. R. (2012). Efficacy of continuously administered PEDF-derived synthetic peptides against osteosarcoma growth and metastasis. Journal of Biomedicine and Biotechnology, 2012. DOI: 10.1155/2012/230298Broadhead, M. L., Dass, C. R. & Choong, P. F. M. (2009). Cancer cell apoptotic pathways mediated by PEDF: prospects for therapy. Trends in Molecular Medicine, 15(10), 461–467. DOI: 10.1016/j.molmed.2009.08.003Broadhead, M. L., Dass, C. R. & Choong, P. F. M. (2009). In vitro and in vivo biological activity of PEDF against a range of tumours. Expert Opinion on Therapeutic Targets, 13(12), 1429–1438. DOI: 10.1517/14728220903307475Broadhead, M. L., Clark, J. C. M., Choong, P. F. M. & Dass, C. R. (2010). Making gene therapy for osteosarcoma a reality. Expert Review of Anticancer Therapy, 10(4), 477–480. DOI: 10.1586/ERA.10.18Broadhead, M. L., Akiyama, T., Choong, P. F. M. & Dass, C. R. (2010). The pathophysiological role of PEDF in bone diseases. Current Molecular Medicine, 10(3), 296–301.Broadhead, M. L., Becerra, S. P., Choong, P. F. M. & Dass, C. R. (2010). The applied biochemistry of PEDF and implications for tissue homeostasis. Growth Factors, 28(4), 280–285. DOI: 10.3109/08977191003604513Broadhead, M. L., Clark, J. C. M., Dass, C. R. & Choong, P. F. M. (2010). Microarray: an instrument for cancer surgeons of the future? ANZ Journal of Surgery, 80(7-8), 531–536. DOI: 10.1111/j.1445-2197.2010.05379.xBroadhead, M. L., Clark, J. C. M., Myers, D. E., Dass, C. R. & Choong, P. F. M. (2011). The molecular pathogenesis of osteosarcoma: a review. Sarcoma, 2011. DOI: 10.1155/2011/959248Broadhead, M. L., Clark, J. C. M., Dass, C. R., Choong, P. F. M. & Myers, D. E. (2011). Therapeutic targeting of osteoclast function and pathways. Expert Opinion on Therapeutic Targets, 15(2), 169–181. DOI: 10.1517/14728222.2011.546351Babazadeh, S., Broadhead, M. L., Slavin, J. L. & Choong, P. F. M. (2009). An interesting diagnosis for a presacral mass: case report. International Seminars in Surgical Oncology, 6(18). DOI: 10.1186/1477-7800-6-18Babazadeh, S., Broadhead, M. L., Slavin, J. L., Schlicht, S. M. & Choong, P. F. M. (2010). Giant cell tumour of metacarpal diaphysis. European Journal of Radiology Extra, 75(1), e31–e36. DOI: 10.1016/j.ejrex.2010.04.008Broadhead, M. L., Babazadeh, S., O'Brien, B. & Choong, P. F. M. (2010). Thigh enlargement and the art of misdirection. ANZ Journal of Surgery, 80(11), 839–840. DOI: 10.1111/j.1445-2197.2010.05503.xBroadhead, M. L., Babazadeh, S., Goldwasser, M. & Choong, P. F. M. (2011). Waxing and waning of joint motion. Grand Rounds, 11, 44–47. DOI: 10.1102/1470-5206.2011.0011Babazadeh, S., Broadhead, M. L. & Choong, P. F. M. (2011). If you are called to lead, you are called to serve. ANZ Journal of Surgery, 81(6), 401–403. DOI: 10.1111/j.1445-2197.2011.05782.xBroadhead, M. L., Babazadeh, S., Ng, K. W., Choong, P. F. M. & Stoney, J. D. (2011). Atraumatic bilateral femoral neck fractures during pregnancy: a missed diagnosis. Australian and New Zealand Journal of Obstetrics and Gynaecology, 51(6), 563-564. DOI: 10.1111/j.1479-828X.2011.01366.xBabazadeh, S., Broadhead, M. L., Schlicht, S. M., Powell, G. J. & Tymms, G. M. (2011). Pathologic fracture of a calcaneal aneurysmal bone cyst. The Journal of Foot and Ankle Surgery, 50(6), 727–732. DOI: 10.1053/j.jfas.2011.04.036Osteosarcoma is the most common primary cancer of bone. Current best treatment consists of chemotherapy and surgery, however many tumours are chemoresistant. Spread of osteosarcoma to the lungs is frequent and is the most common cause of death. This thesis examines the role of pigment epithelium-derived factor (PEDF) in the processes of osteosarcoma growth, invasion and metastasis. In order to evaluate this potential role, both in vitro and in vivo studies have been performed. In vitro studies have examined the biological effects and mechanisms of PEDF. PEDF exhibits a multifaceted ability to inhibit osteosarcoma tumorigenicity. PEDF inhibits proliferation, induces apoptosis and reduces cell cycling of osteosarcoma cells in vitro. Additionally, the metastatic capacity of osteosarcoma cell lines is diminished by PEDF. Osteosarcoma cells treated with PEDF demonstrate an enhanced capacity for adhesion and a reduced ability for invasion through collagen I, the most abundant protein in bone. An established murine model of orthotopic osteosarcoma has been optimised for the evaluation of novel therapeutic agents in vivo. This model allowed for an evaluation of systemically delivered PEDF and PEDF-derived peptides, both as sole treatments and in combination with doxorubicin. Systemic administration of PEDF causes a reduction in both primary tumour volume and pulmonary metastatic disease. PEDF-derived peptides, StVOrth-2 (residues 78-102) and StVOrth-3 (residues 90-114) were also delivered systemically. StVOrth-2 primarily restricts growth of primary osteosarcoma while StVOrth-3 restricts pulmonary metastatic disease. Finally, advanced medical imaging techniques have been applied to this murine model of orthotopic osteosarcoma for the study of tumour growth, invasion and metastasis; in vivo bioluminescent imaging, [18F]-Fluoride-PET, [18F]-FDG-PET and micro-computed tomography provide novel information about this model. Use of these imaging modalities has improved osteosarcoma modelling and allowed closer monitoring of disease progression. This is the first time that in vivo imaging has been used in the assessment of PEDF’s anti-osteosarcoma properties and is a major advance from previously published studies demonstrating direct effects on osteosarcoma growth and metastasis