Osteosarcoma (OS) is the most prevalent aggressive primary malignancy of the bone affecting children and young adults. Approximately 10% to 20% of patients have metastatic disease at initial presentation. The most common site for disease metastasis and recurrence is the lungs. Although overall survival in patients with OS has improved with advances in therapy, there have been no significant improvements in survival outcome in patients with metastatic disease, and the prognosis is grim. Due to the complex genetic heterogeneity of OS, molecular targeted approaches are not feasible. For this reason, novel therapeutic approaches are desperately needed. Recent studies suggest that tumor-associated Vascular Cell Adhesion Molecule-1 (tVCAM-1) plays a critical role in the metastatic progression of various tumors. Indirect evidence from these studies suggest that VCAM-1/ α4ß1 integrin signaling promotes tumor survival and metastatic progression by changing the tumor niche and associated immune response.
Our preclinical data using spontaneous, high-grade murine OS cell lines, K7 and K7M2 (derived from in vivo K7 metastasis) from Balb/c mice (H-2d), support the idea that interference of VCAM-1/ α4ß1 signaling between pulmonary metastatic osteosarcoma (pOS) and lung macrophages (MACs) reduces pOS. This can be achieved by down-regulating VCAM-1, depleting MACs or functionally blocking VCAM-1/ α4ß1 signaling. Our data supported the development of our Phase I/II clinical trial using immunotherapy as a therapeutic option for children, adolescent and young adult patients with pOS. We plan to elucidate more information regarding the tumor microenvironment from patients enrolled on our clinical trial by examining tumor pathology and soluble VCAM-1 concentration in peripheral blood. Further understanding of the mechanisms underlying VCAM-1/α4β1 signaling will provide critical insight into the molecular regulatory pathway that serves as the foundation for our clinical trial, and for our next anticipated trial using immunotherapy in conjunction with metronomic chemotherapy. Continued efforts in our lab also focus on the use of TGF-β inhibitor and a β-glucan-type immune modulator to reduce regression of tumor growth and pulmonary lung metastasis. These novel possibilities may highly impact the survival of pediatric and adolescent and young adult patients with pOS by offering real clinical opportunities for treatment.