A Review of Targeted Therapies Evaluated by the Pediatric Preclinical Testing Program for Osteosarcoma

Abstract

Osteosarcoma, the most common malignant bone tumor of childhood, is a high-grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical endpoints for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early-phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP) has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.

Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial

“…Consequently, small inhibitors as imatinib and monoclonal antibodies as trastuzumab), bevacizumab13 and anti-Insulin-like Growth Factor-1 Receptor (IGF-1R) 13,14 have been tested without evidence of significant activity in advanced HG-OS. In this context, phospho-extracellularregulated kinase 1/2 (P-ERK1/2) were shown to be involved into HG-OS growth, survival, neoangiogenesis and metastatic potential 15,16 .…”

Systematic Screening Identifies Dual PI3K and mTOR Inhibition as a Conserved Therapeutic Vulnerability in Osteosarcoma

“…To date, research has led to only a limited number of clinically relevant biologic insights (9,10). Empirical evaluation of novel agents in human xenografts has not to date yielded any major translational advances (10).…”

“…Empirical evaluation of novel agents in human xenografts has not to date yielded any major translational advances (10). The only agent to show promise from these studies has been mTOR inhibitors such as rapamycin (11).…”

Chloroquine and Valproic Acid Combined Treatment in Vitro has Enhanced Cytotoxicity in an Osteosarcoma Cell Line

“…It is the most frequent type of bone tumor between the ages of 15 to 25.The most common sites are the bones around the knee (Chen et al, 2013;Liu et al, 2013;Sampson et al, 2013;Sangsin et al, 2013). Although extensive efforts have been made in anti-osteosarcoma therapy in recent years, there are still no effective lowtoxicity drugs for treating osteosarcoma.…”

“…The common malignant bone tumor, especially in children and adolescents, is osteosarcoma Liu et al, 2013;Sampson et al, 2013). However, in present clinical therapeutic method, chemotherapy is still in low efficiency and causegreat pain to the patient (Chen et al, 2013;Sangsin et al, 2013).…”