Advances in the Treatment of Pediatric Bone Sarcomas

Abstract

OVERVIEW Bone tumors make up a significant portion of noncentral nervous system solid tumor diagnoses in pediatric oncology patients. Ewing sarcoma and osteosarcoma, both with distinct clinical and pathologic features, are the two most commonly encountered bone cancers in pediatrics. Although mutations in the germline have classically been more associated with osteosarcoma, there is recent evidence germline alterations in patients with Ewing sarcoma also play a significant role in pathogenesis. Treatment advances in this patient population have lagged behind that of other pediatric malignancies, particularly targeted interventions directed at the biologic underpinnings of disease. Recent advances in biologic and genomic understanding of these two cancers has expanded the potential for therapeutic advancement and prevention. In Ewing sarcoma, directed focus on inhibition of EWSR1-FLI1 and its effectors has produced promising results. In osteosarcoma, instead of a concentrated focus on one particular change, largely due to tumor heterogeneity, a more diversified approach has been adopted including investigations of growth factors inhibitors, signaling pathway inhibitors, and immune modulation. Continuing recently made treatment advances relies on clinical trial design and enrollment. Clinical trials should include incorporation of biological findings; specifically, for Ewing sarcoma, assessment of alternative fusions and, for osteosarcoma, stratification utilizing biomarkers. Expanded cancer genomics knowledge, particularly with solid tumors, as it relates to heritability and incorporation of family history has led to early identification of patients with cancer predisposition. In these patients through application of cost-effective evidence-based screening techniques the ultimate goal of cancer prevention is becoming a realization.

Emerging trends in immunotherapy for pediatric sarcomas

“…Bony matrix remodeling is a unique feature of pediatric bone sarcomas contributing to the significant genetic and TME heterogeneity that new treatments must overcome [16, 17]. One of the prominent mediators of this remodeling is the receptor activator NFκB ligand (RANKL), RANK, and osteoprotegerin (OPG) system [18].…”

Glutamine synthetase is necessary for sarcoma adaptation to glutamine deprivation and tumor growth

“…Despite a growing body of knowledge about the genomic landscape and molecular pathogenesis of RMS and ES, the successful translation of basic discoveries into molecularly targeted therapies and significant clinical gains has remained elusive 8,10,11 . There are relatively few recurrent genetic mutations driving tumorigenesis for the majority of pediatric sarcomas, and ES tumors possess one of the lowest somatic mutation rates among all human cancers (0.15 mutations/megabase) 8,11,12 . Rather, approximately one-third of all sarcomas are driven by chimeric transcription factors, which are the result of well-defined chromosomal translocations 1,11 .…”

“…Indeed, this is especially true of ES and the most aggressive form of RMS. These oncogenic, chimeric transcription factors are extremely challenging drug targets due to disordered protein structure and lack of intrinsic enzymatic activity 8,12 .…”

Impacts of Pharmacists-Managed Oncology Outpatient Clinic on Resolving Drug-Related Problems in Ambulatory Neoplasm Patients: A Prospective Study in China

“…In recent years, the combination of high-dose ifosfamide, high-dose methotrexate, anthracycline, and cisplatin has been recognized as effective chemotherapy regimens for bone and soft tissue tumors. 21 , 22 Constipation, rash and diarrhea are also common adverse reactions that require face-to-face evaluation for diagnosis and real-time treatment with medications. In particular, 78.2% of the adverse reactions were improved by the pharmacist interventions and suggested medications.…”