Defining the mechanisms of chemotherapy resistance in childhood and adolescent osteosarcoma.

Osteosarcoma is the most prevalent primary malignant tumour of the bone, mainly affecting teenagers and young adults, particularly during growth spurts. Incorporation of neoadjuvant chemotherapy has increased 5-year survival rates from 10% to ~70% for patients with localised disease. However, ~20% of patients present with metastases at diagnosis and a further 25%-50% will develop metastatic disease during their treatment. Despite aggressive multimodal treatments including polychemotherapy (typically methotrexate, doxorubicin and cisplatin [MAP]), surgery, and radiation therapy (where applicable if complete surgical resection is not possible), cure rates for patients with metastatic or relapsed disease are poor, with a 5-year survival rate of <20% and represent a significant clinical challenge. Alarmingly, these survival rates have remained unchanged for decades highlighting the urgent need for improved therapeutic strategies. Aside from disease at diagnosis, the histological response to induction chemotherapy is the gold standard indicator for patients with osteosarcoma, assessed by percentage of necrotic tissue using the Huvos grading system. However, individual patients’ response to induction chemotherapy is variable suggesting inherent resistance and to date there is no reliable way to predict which patients will respond to therapy. Through direct engagement with sarcoma patients and their families, and via the Australian and New Zealand Sarcoma Association (ANZSA) we have identified two major areas of unmet need and consumer-guided priorities: improved therapeutic strategies to reduce toxicities; and more accurate prognostication to guide individual patient clinical management. This project will work to bridge this gap in translation, by better understanding osteosarcoma biology to identify the mechanisms and molecular signatures of patient response to therapy, and therapeutic strategies to improve response, that will ultimately improve patient survival and survivorship. Using a functional genomics approach in clinically relevant preclinical models and osteosarcoma patient tissues we will determine the genetic, epigenetic and molecular events underpinning chemo resistance, and identify and validate therapeutic opportunities to overcome resistance. Please email me directly with enquiries: jason.cain@hudson.org.au.