Future directions in the treatment of osteosarcoma

Abstract

Purpose of Review Overall survival rates for osteosarcoma have remained essentially unchanged over the past three decades despite attempts to improve outcome via dose intensification and modification based on response. This review describes recent findings from contemporary clinical trials, advances in comprehension of osteosarcoma biology and genomic complexity, and potential opportunities using targeted and immune-mediated therapies. Recent Findings Recent results from international collaborative trials have failed to demonstrate an ability to improve outcomes using a design in which the randomized question is dictated based on histologic response to preoperative chemotherapy. Novel prognostic markers assessable at diagnosis are vital to identifying subsets of osteosarcoma. Clinical trials focus has now shifted to serial phase II studies of novel agents to evaluate for activity in recurrent and refractory disease. In-depth analyses have revealed profound genomic instability and heterogeneity across patients, with nearly universal TP53 aberration. While driver mutational events have not clearly been established, frequent derangements in specific pathways may suggest opportunities for therapeutic exploitation. Genomic complexity may lend support to a role for immune-mediated therapies. Summary Rigorous preclinical investigations are potentially generating novel strategies for treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes.

Bruceine D inhibits tumor growth and stem cell‐like traits of osteosarcoma through inhibition of STAT3 signaling pathway

“…The advent of adjuvant therapies and advances in surgical techniques, have caused the overall survival rates of osteosarcoma patients to reach 60%‐75% . However, the 5‐year survival rate for those with metastasis remains less than 30% and is almost unchanged over the past three decades .…”

“…Osteosarcoma, which occurs predominantly in children and adolescents, is the most common type of primary bone malignancy . With the advent of chemotherapy and advances in surgical technology, the 5‐year survival rates for patients with local osteosarcoma have significantly improved, attaining 70% . Unfortunately, cure rate has not improved significantly over the past 30 years.…”

miRNA profiling identifies deregulated miRNAs associated with osteosarcoma development and time to metastasis in two large cohorts

“…This has been demonstrated for ependymomas (Mack et al, 2014) and more recently Ewing sarcoma (Sheffield et al, 2017), which are characterized by no or the same recurrent genetic aberration, respectively. The genetic components of OS have been intensively studied (Bishop et al, 2016;Kansara et al, 2014); however, the elucidation of the epigenetic changes is still in its early stage. Gene expression is regulated by numerous mechanisms and molecules, including microRNAs (miRNAs).…”

The interaction between RUNX2 and core binding factor beta as a potential therapeutic target in canine osteosarcoma

“…The treatment for osteosarcoma (OSA) has remained unchanged since the addition of adjuvant cytotoxic chemotherapy regimens (consisting of methotrexate, doxorubicin and cisplatin/carboplatin) to amputation or limb‐sparing approaches in the late 1970s . Although these advances on OSA treatment represented an improvement of the survival rates in dogs and humans in the non‐metastatic disease setting, 10% to 15% after 2 years and 65% to 70% after 5 years, respectively, little advancements have been achieved in patients with metastatic and/or relapsed disease despite great efforts to improve the prognosis in these patients through treatment intensification . Hence, there is an unmet need to find new therapeutic targets in order to increase the survival rates not only in patients with metastatic OSA but also with non‐metastatic disease.…”