Advances in Osteosarcoma

Abstract

Purpose of review: This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease.

Recent findings: Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme. The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.

Keywords: Immune checkpoint inhibitor; Immunotherapy; Osteosarcoma; Personalized medicine; Tumor microenvironment; Tumor targeted therapy.

Fig. 1

New therapeutic approaches based on RANK/RANKL/OPG signaling. The RANKL/RANK/OPG pathway controls osteoclastogenesis and orchestrates bone remodeling. RANKL expressed at the surface of osteoblasts and in a soluble form binds to RANK expressed by osteoclast precursor membranes leading to osteoclast differentiation and bone resorption. OPG acts as a decoy receptor in this system and interrupts RANK-RANKL binding and signaling, and consequently inhibits bone resorption. Combined anti-RANKL therapy with macitentan, an inhibitor of both ETA-B endothelin receptors, was associated with a decrease in lung metastases, as well as a bone protective reaction in a preclinical OS murine model

Fig. 2

Targeting of Wnt signaling in OS. OS is characterized by heterogeneity in the expression of Wnt ligands and receptors. Due to their over-activation in OS, the transcriptional targets of Wnt/β-catenin are associated with pathways responsible for OS progression. Among these pathways modulated by Wnt/β-catenin, cyclin D1 and survivin are involved in cell proliferation, runx2 in osteogenic differentiation, and RANKL in osteoclast activation. The ICG-001 derivative PRI-724 inhibits cell proliferation due to the blockade of the CREB binding protein (CBP)/β-catenin complex formation in vitro. The parathyroid hormone (PTH) and its parathyroid hormone receptor 1 (PTHR1) activate the Wnt/β-catenin pathway in OS cells. Long non-coding RNA LINC01278 expressed in the cytoplasm of OS cells blocks miR-133a-3p, a tumor inhibitor molecule of PTHR1, promoting the upregulation and release of PTHR1, and may serve as an oncogene in OS development. Convallatoxin downregulates the expression of PTHR1

Fig. 3

Ferroptosis in OS cells. Ferroptosis is a programmed cell death pathway related to reactive oxygen species (ROS) accumulation. SLC7A11 is a cystine/glutamate antiporter that regulates ferroptosis by controlling the synthesis of GSH, affecting the GSH-GXP4 axis. In OS cells, activation of the p53 gene downregulates the expression of SLC7A11 leading to a tumor suppressor effect. The lncRNA SNHG14 is upregulated in OS cells, downregulates expression of miR-206, affecting the ferroptosis inhibitor SLC7A11, preventing ferroptosis. Sulfasalazine (SAS) and tirapazamine (TPZ) are inhibitors of the cystine/glutamate system affecting GPx4 activity and the consequent accumulation of ROS. microRNA-1287-5p inhibits the inhibition of GPX4, enhancing OS cell death via ferroptosis

Fig. 4

PD-1 in OS cells. PD-1 is a transmembrane protein that acts as an immune checkpoint receptor that is expressed in CD4⁺ and CD8⁺ T cells. The interaction with their ligand PD-L1 downregulates T cells leading to an adaptive immune tolerance. PD-1 inhibitors such as pembrolizumab, nivolumab, and cemiplimab, and PD-L1 inhibitors such as atezolizumab, avelumab, and durvalumab are currently approved by the FDA

Fig. 5

CTLA-4 in OS cells. The cytotoxic T cell lymphocyte antigen 4 (CTLA-4) is expressed on regulatory T cells and is a co-inhibitory receptor for CD28 for its B7 ligands during T cell activation. CTLA-4 is expressed in OS cells leading to immune system evasion. Ipilimumab, anti-CTLA-4 antibody, and tremelimumab (Anti-CTLA-4) were tested in clinical trials in combination with anti-PD-L1/PD-1 antibodies in sarcoma subtypes

Fig. 6

TIM-3 in OS tumors. The receptor T cell immunoglobulin and mucin-containing protein-3 (TIM-3) expressed on type 1 T helpers binds to their ligand galactin-9 (Gal-9), inducing Th1 apoptosis and tolerance of T cells in the OS tumor microenvironment