Osteosarcoma is the most common primary malignancy of bone, with a peak incidence during the second decade of life. While patient outcomes improved with the addition of a chemotherapy regimen to standard surgical resection, outcomes have been static for decades and remain poor. Patients with metastases, almost always to the lung, have a five year survival rate of less than 30% despite the use of aggressive chemotherapy including high-dose methotrexate, cisplatin, and doxorubicin. It is clear that metastasis is a critical obstacle to the improvement o patient outcomes and survival. Here, we propose to investigate the molecular mechanisms by which osteosarcoma metastasis occurs. Specifically, we will examine the contribution of an intracellular signaling complex comprised of the CARMA3, Bcl10 and MALT1 proteins in promoting these processes in osteosarcoma, with the hopes of identifying novel therapeutic approaches for treating our patients. We propose two independent Specific Aims: In the first aim, we will investigate molecular mechanisms by which the osteosarcoma tumor microenvironment can promote metastasis. Then in the second aim, we will evaluate MALT1 as a new potential therapeutic target for the treatment of metastatic osteosarcoma. The principal investigator of this proposal is a physician scientist in training who is pursuing a career focused on pediatric oncology, with a special interest in sarcoma research. The proposed research plan, along with a well-structured training plan that includes mentoring from accomplished leaders in the fields of pediatric oncology, pathology, pediatric orthopedic oncologic surgery, and phase I clinical trial design, will lay the groundwork to allow this applicant to launch an extraordinarily promising career in childhood cancer research.
While the treatment of osteosarcoma, a cancer of the bone that primarily affects adolescents, has improved, patients that develop osteosarcoma metastases still face an extremely poor outlook with fewer than 30% of patients surviving for more than five years. This project aims to address gaps in our understanding of how and why osteosarcoma spreads. Most importantly, we have identified an intracellular signaling pathway that we believe contributes to this aggressive behavior and expect that further characterization of this pathway will help us to identify new therapeutic targets to exploit in combating this devastating childhood cancer.
